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Library of Congress Cataloging-in-Publication Data

Ajjan, Ramzi.

Endocrinology and diabetes : clinical cases uncovered / Ramzi Ajjan.

p. ; cm.

Includes index.

ISBN 978-1-4051-5726-1

1. Endocrinology - Case studies. 2. Diabetes - Case studies. I. Title.

[DNLM:

1. Endocrine System Diseases - diagnosis - Case Reports.

2. Diabetes Mellitus -

diagnosis - Case Reports.

3. Diabetes Mellitus - therapy - Case Reports.

4. Endocrine System

Diseases - therapy - Case Reports. WK 140 A312e 2009]

RC649.5.A35 2009

616.4 - dc22

2008033368

ISBN: 978-1-4051-5726-1

A catalogue record for this book is available from the British Library.

Set in 9/12pt Minion by SNP Best-set Typesetter Ltd., Hong Kong

Printed and bound in Singapore by Ho Printing Singapore Pte Ltd

2009

Contents

Preface, vii

Acknowledgements, viii

How to use this book, ix

List of abbreviations, x

Part 1 Basics, 1

The pituitary gland, 1

The thyroid, 13

Bone and calcium metabolism, 23

The adrenal glands, 30

The reproductive system, 36

The pancreas, 46

Lipid abnormalities and obesity, 60

The neuroendocrine system, 63

Part 2 Cases, 66

Case 1 A 19-year-old with abdominal pain and vomiting, 66

Case 2 A 35-year-old woman with palpitation and irritability, 73

Case 3 A 61-year-old man with polyuria, polydipsia, cough and weight loss, 79

Case 4 A 44-year-old woman with visual problems, 82

Case 5 A 20-year-old man with recent diagnosis of diabetes, 86

Case 6 Tiredness and weight gain in a 30-year-old woman with diabetes, 89

Case 7 Acute confusion in an 82-year-old with known type 2 diabetes, 92

Case 8 A 42-year-old man with headaches, increased sweating and sexual dysfunction, 98

Case 9 Amenorrhoea in an 18-year-old, 102

Case 10 A 28-year-old with tiredness and abnormal thyroid function postpartum, 106

Case 11 A 33-year-old man with polyuria and polydipsia, 109

Contents

Case 12 A 62-year-old man with tiredness and hyponatraemia, 113

Case 13 Excess hair in a 29-year-old woman, 117

Case 14 A 52-year-old woman with paroxysmal atrial fibrillation and abnormal thyroid

function, 120

Case 15 A 22-year-old man with hypertension, 123

Case 16 A 20-year-old woman with polyuria and polydipsia, 126

Case 17 A 78-year-old man with pain in the leg and knee, 132

Case 18 A 32-year-old woman with a lump in the neck, 135

Case 19 A 26-year-old with headaches and hypertension, 139

Case 20 Sweating, nausea and hand tremor in a 24-year-old woman, 142

Case 21 A 19-year-old man with sexual dysfunction, 146

Case 22 A 38-year-old woman with muscular aches and weakness, 151

Case 23 A wrist fracture in a 56-year-old woman, 154

Case 24 A 37-year-old woman with recurrent flushing, 158

Case 25 A 46-year-old man with an abnormal lipid profile, 161

Part 3 Self-assessment, 164

MCQs, 164

EMQs, 169

SAQs, 174

Answers, 176

Index of cases by diagnosis, 187

Index, 189

Colour plate section can be found facing p. 84.

Preface

Almost two decades have passed since my medical student

diabetes and endocrine conditions is provided, including

days and I still remember how difficult, and often tedious,

basic science, symptoms and signs, investigations and

it was to read and understand some of the clinical topics

treatment.

presented in textbooks.

In Part 2, diabetes and endocrinology are covered

Having been fortunate enough for my career to develop

using ‘real life’ cases, which I encountered during my

in academic medicine, part of my work involves regular

clinical practice. Each case is divided into a number of

teaching and lecturing at different levels, ranging from

sections/questions, which you should read carefully and

medical students to experienced physicians and health

make an attempt to give a differential diagnosis or for-

care professionals.

mulate a management plan. You will notice I have varied

Despite a variety of audience, there has always been a

the amount of background information, depending on

general enthusiasm for further learning when clinical

the importance and the prevalence of the medical condi-

tutorials/lectures were not only presented as ‘facts’ but

tion under discussion. In common clinical scenarios,

also as case-based studies. Moreover, I realised during my

comprehensive management plans are given, whereas in

clinical practice that various medical conditions are best

less common and more specialised cases, diagnostic and

remembered by discussing and fully evaluating real life

treatment strategies are only briefly touched upon. Take

cases. Putting things together, I felt a case-based book

your time with each case and remember that these are

would offer a unique opportunity to facilitate under-

real life cases, which you may be attending to as a junior

standing of clinical diabetes and endocrinology, and

medical doctor.

make the learning process an enjoyable experience.

In Part 1 of the book, a simple reminder of clinical

Ramzi Ajjan

vii

How to use this book

Clinical Cases Uncovered (CCU) books are carefully

test your learning with several question styles (MCQs,

designed to help supplement your clinical experience and

EMQs and SAQs), each with a strong clinical focus.

assist with refreshing your memory when revising. Each

Whether reading individually or working as part of a

book is divided into three sections: Part 1, Basics; Part 2,

group, we hope you will enjoy using your CCU book.

Cases; and Part 3, Self-Assessment.

If you have any recommendations on how we could

Part 1 gives a quick reminder of the basic science,

improve the series, please do let us know by contacting

history and examination, and key diagnoses in the area.

us at: medstudentuk@oxon.blackwellpublishing.com.

Part 2 contains many of the clinical presentations you

would expect to see on the wards or crop up in exams,

Disclaimer

with questions and answers leading you through each

CCU patients are designed to reflect real life, with their

case. New information, such as test results, is revealed as

own reports of symptoms and concerns. Please note that

events unfold and each case concludes with a handy case

all names used are entirely fictitious and any similarity to

summary explaining the key points. Part 3 allows you to

patients, alive or dead, is coincidental.

List of abbreviations

ABG

arterial blood gas (analysis)

5HIAA

5-hydroxyindolacetic acid

ACEI

angiotensin converting enzyme inhibitors

HNF

hepatic nuclear factor

ACR

albumin/creatinine ratio

HMG

CoA 3-hydroxy, 3-methylglutaryl coenzyme A

ACTH

adrenocorticotrophic hormone

HONK

hyperosmolar non-ketotic hyperglycaemia

autosomal dominant

HRT

hormone replacement therapy

ADH

antidiuretic hormone

IHD

ischaemic heart disease

autoimmune hypothyroidism

IHH

idiopathic hypogonadotrophic hypogonadism

alkaline phosphatase

IST

insulin stress test

autosomal recessive

IUI

intrauterine insemination

ARB

angiotensin receptor blocker

i.v.

intravenous

BMD

bone mineral density

IVF

in vitro fertilization

BMI

body mass index

LADA

latent autoimmune diabetes of adults

CAH

congenital adrenal hyperplasia

LDLc

low-density lipoprotein cholesterol

CCF

congestive cardiac failure

LDST

low dose synacthen test

CRH

corticotrophin releasing hormone

LFT

liver function test

CRP

C-reactive protein

luteinizing hormone

computed tomography

MEN

multiple endocrine neoplasia

CVA

cerebrovascular accident

MIBG

meta-iodobenzylguanidine

DEXA

dual energy X-ray absorptiometry

MODY

maturity onset diabetes of the young

DHEA

dehydroepiandrosterone

MRA

magnetic resonance angiography

diabetes insipidus

MRI

magnetic resonance imaging

DKA

diabetic ketoacidosis

MTC

medullary thyroid cancer

DOC

deoxycorticosterone

neurofibromatosis

DPP

dipeptidyl peptidase

OCP

oral contraceptive pill

ECG

electrocardiogram

OGT

oral glucose tolerance (test)

ESR

erythrocyte sedimentation rate

PCOS

polycystic ovary syndrome

FBC

full blood count

pulmonary embolus

FHH

familial hypocalciuric hypercalcaemia

PRA

plasma renin activity

FNA

fine needle aspiration

PRL

prolactin

FSH

follicle stimulating hormone

PSA

prostate specific antigen

GAD

glutamic acid decarboxylase

PTH

parathyroid hormone

GGT

gamma glutamyl transpeptidase

RAI

radioactive iodine

growth hormone

SHBG

sex hormone binding globulin

GHRH

growth hormone releasing hormone

SIADH

syndrome of inappropriate ADH secretion

GLP

glucagon-like peptide

total cholesterol

GnRH

gonadotrophin releasing hormone

T1DM

type 1 diabetes mellitus

Graves’ ophthalmopathy

T2DM

type 2 diabetes mellitus

GST

glucagon stimulation test

TFT

thyroid function test

hCG

human chorionic gonadotrophin

thyroglobulin

The pituitary gland

Understanding the pituitary gland is probably the hardest

Antidiuretic hormone

(ADH): stimulates water

part of endocrinology as it controls most of the endocrine

reabsorption by the kidneys

glands in the body and disease may arise due to both over-

Oxytocin: helps uterine contractions during labour

secretion and undersecretion of a particular hormone. A

The anterior pituitary gland is under the control of the

full understanding of the hormonal tests in this section

hypothalamus as shown in Fig. 3.

will make interpretation of the endocrine tests in the rest

• Corticotrophin releasing hormone (CRH): stimulates

of the book an easy and pleasant experience.

ACTH secretion

• Growth hormone releasing hormone (GHRH): stimu-

Anatomy

lates GH secretion

The pituitary gland is situated in the pituitary fossa and

• Thyrotrophin releasing hormone (TRH): stimulates

is surrounded by (see Fig. 1):

TSH secretion

• Below: sphenoid air sinus

• Gonadotrophin releasing hormone (GnRH): stimu-

• Either side: cavernous sinus and carotid artery

lates FSH and LH secretion

• Above: the pituitary stalk extending into the

• Prolactin releasing hormone does not exist and prolac-

hypothalamus

tin is under the inhibitory effect of the hypothalamus

Cortisol, GH, thyroid hormones and sex hormones all

Physiology

have a negative feedback effect on corresponding

The pituitary gland can be functionally divided into two

pituitary (ACTH, GH, TSH and FSH/LH respectively)

lobes (Fig. 2)

and hypothalamic

(CRH, GHRH, TRH and GnRH

• The anterior pituitary, which produces the following

respectively) hormone release.

hormones

Growth hormone

(GH): resulting in skeletal

Clinical disease

growth

Clinical disease results from oversecretion or undersecre-

Adrenocorticotrophic hormone (ACTH): stimulates

tion of pituitary hormones, in addition to the local com-

the adrenals to produce steroids

pressive effects of a pituitary tumour. A pituitary tumour

Gonadotrophins (FSH and LH): stimulate the testi-

may secrete excessive hormones but it may also be non-

cles or ovaries to produce sex hormones

functional, in which case the clinical presentation

Thyroid stimulating hormone or thyrotrophin

consists of pituitary failure associated with compressive

(TSH): stimulates the thyroid to produce thyroid

effects.

hormones

Prolactin (PRL): stimulates breast milk production

Pituitary oversecretion

• The posterior pituitary, which stores the hormones

• Usually due to pituitary tumours overproducing one

produced in the hypothalamus

(does not produce

hormone (sometimes more than one) resulting in typical

them)

clinical entities, which are described below

• Very rarely, overproduction of pituitary hormones

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

may be due to increased production of pituitary hormone

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

releasing hormones (CRH, GHRH)

Part 1: Basics

Pituitary

Optic nerve

Carotid artery

Sphenoid crest

Sphenoid sinus

Sphenoid sinus ostium

Maxillary sinus

Vomer

Figure 1 Position of the pituitary gland.

Paraventricular nuclei

Supraoptic nuclei

Hypothalamic /

Optic chiasm

hypophyseotropic area

Superior hypophyseal

Primary capillary plexus

artery

Median eminence

Pituitary stalk

Hypophyseal portal

Supraoptic -

vessels

hypothalamic tract

Anterior pituitary

Posterior pituitary

Secretory cells

Capillaries

Efferent veins

Figure 2 Two lobes of the pituitary

gland. From Holt, RIG & Hanley, NA

Efferent veins

(2007) Essential Endocrinology and

Inferior hypophyseal

Diabetes, 5^th edition. Blackwell

artery

Publishing, Oxford.

Hypothalamus

GHRH

CRH

TRH

GnRH

Pituitary failure

• Acquired pituitary hormonal deficiency is commonly

Pituitary

ACTH

TSH

FSH/LH

due to a pituitary tumour compressing and compromis-

ing the activity of normal cells

• It may also be secondary to:

Developmental abnormalities

Liver

Adrenals

Thyroid

Ovary/testicle

(IGF-1)

(steroids)

(T3 and T4)

(sex hormones)

Autoimmune conditions

Head injury

Figure 3 Control of hormone secretion by the hypothalamus

Vascular disorders and severe blood loss (resulting

and pituitary (see text). GHRH, CRH, TRH and GnRH, secreted

in infarction of the pituitary)

by the hypothalamus, stimulate GH, ACTH, TSH and FSH/LH

Infiltrative disease and infection

(sarcoidosis,

production by the pituitary respectively, which in turn

tuberculosis)

stimulate the liver, adrenal glands, thyroid and ovaries/testicles

Radiotherapy

to produce their hormones. GH, adrenal steroids, thyroid

• It should be noted that pituitary hormonal deficiency

hormones and sex steroids in turn have a negative feedback

commonly involves multiple hormones and, therefore,

effect (reduce hormone production) on the corresponding

deficiency of one hormone warrants full pituitary

hypothalamic/pituitary hormone release. The pituitary hormone

prolactin (which is not shown here) is unique as there is no

investigations.

hypothalamic hormone to stimulate its release but it is rather

• Local effects of all pituitary tumours include:

under inhibitory control.

Headaches

The pituitary gland

Visual field defects (usually bitemporal hemianopia)

• High sex steroids with elevated gonadotrophin suggest

Deficiency of other hormones (due to pressure effect

gonadotrophin-secreting pituitary tumour

(these are

on normal pituitary tissue)

rare and often clinically silent)

Cranial nerve palsies:

3rd,

4th and 6th in large

• Low sex hormones with raised gonadotrophins, indi-

pituitary tumours

cate primary gonadal failure and this is seen in physio-

logical menopause (women above the age of 50 usually

Investigations of the pituitary gland

have raised gonadotrophin levels with low oestradiol)

This involves investigations of hormonal abnormalities

Prolactin

and imaging of the pituitary gland.

• Raised serum prolactin may be due to a pituitary pro-

lactinoma (this is fully discussed later in this chapter)

Hormonal investigation of suspected pituitary

hormone abnormality

Stimulation tests in suspected hypopituitarism

In general, there are three ways to investigate hormonal

The two main stimulation tests used are:

abnormalities in endocrine disease:

• Static hormone measurements: this is a “one off ” mea-

Insulin stress test

surement of a particular hormone. Examples include

• This is the gold standard test to assess pituitary func-

measurement of thyroid function (TSH and T4), gonadal

tion but it has a number of contraindications (see below)

function (sex steroids and gonadotrophins) and mea-

and therefore it is not always used first line

surement of prolactin

• Insulin injection results in hypoglycaemia creating a

• Stimulation tests: if deficiency of a particular hormone

stressful environment with consequent release of ACTH

is suspected, stimulation tests are carried out. Failure of

and GH

a particular hormone level to rise after stimulation tests

• 0.1-0.3 U/kg of insulin is injected

(high doses are

confirms hormonal deficiency. Examples include growth

required in those with insulin resistance) to render the

hormone and cortisol deficiency

patient hypoglycaemic and GH/cortisol are measured

• Suppression test: if oversecretion of a hormone is sus-

• GH >20 mIU/L and cortisol >580 nmol/L indicate

pected, suppression tests can be carried out. Failure of

adequate hormonal reserve

suppression of a particular hormone indicates overpro-

• Contraindications

duction. Examples include growth hormone oversecre-

History of epilepsy

tion (acromegaly) and ACTH oversecretion (Cushing’s

Abnormal ECG or ischemic heart disease

disease)

Untreated hypothyroidism

Basal cortisol < 100 nmol/L

Static pituitary function tests

Thyroid function tests (TFTs)

Glucagon stimulation test

• Low free T4 (FT4) with low or low normal TSH:

• Injection of glucagon results in:

This should alert to the possibility of pituitary

Release of growth hormone and ACTH

(GH

failure

>20 mIU/L or cortisol >580 nmol/L indicate normal

Differential diagnosis includes abnormal TFTs due

GH and ACTH reserve)

to non-thyroidal illness

(described in the thyroid

• The test is not always reliable (up to 20% of normal

section)

individuals fail to fully respond) and in case of any doubts

• Raised TSH and raised FT4: possible TSH-secreting

insulin stress test should be performed

pituitary tumour

• Contraindications

• Raised TSH with low or normal FT4: primary

The test is less reliable in subjects with diabetes

hypothyroidism

• Suppressed TSH with high or normal FT4: primary

Other stimulation tests

hyperthyroidism

• These are quite specialized and beyond the scope of

Sex hormones (testosterone or oestradiol)

this book and include:

• Low sex hormones with low or low normal gonadotro-

TRH stimulation test

phins (FSH and LH) should raise the possibility of pitu-

GnRH stimulation test

itary failure

Arginine stimulation test

Part 1: Basics

Table 1 Main tests for pituitary functions.

Static tests

Stimulation tests

Suppression tests

Thyroid function tests

Insulin stress test

Glucose tolerance test

Low FT4 and low or low-normal TSH

Failure of GH and cortisol to rise after

Failure of GH suppression after oral GTT

suggests hypopituitarism

insulin injection suggests

suggests GH oversecretion (acromegaly)

hypopituitarism

Sex hormones

Glucagon stimulation tests

Low- and high-dose dexamethasone

Low sex hormones with low or low-normal

Failure of GH and cortisol to rise after

suppression test

gonadotrophins suggests hypopituitarism

glucagon injection suggests

(see text)

hypopituitarism

Prolactin

Raised prolactin suggests pituitary

prolactinoma

Suppression tests in suspected hormonal

• High levels of pituitary hormones in the petrosal sinus

overproduction

compared with a peripheral vein, confirm the diagnosis

Oral glucose tolerance test

of pituitary secreting hormones

• This is used in suspected GH oversecretion

The test is often used to differentiate pituitary-

Failure to suppress GH to <2 mIU/L after 75 g oral

dependent Cushing’s disease from ectopic ACTH

glucose tolerance test strongly suggests the diagnosis of

secretion. Higher ACTH levels in the petrosal sinus

acromegaly

compared with venous ACTH, after CRH stimulation

confirms pituitary-dependent Cushing’s disease

Dexamethasone suppression test

• This is used to diagnose Cushing’s syndrome but may

Treatment

also be able to differentiate between pituitary and non-

• Non-functioning pituitary tumours or those associ-

pituitary causes of Cushing’s syndrome

ated with increased hormone production (except for

Low dose dexamethasone suppression test: failure to

prolactinomas, see below) are usually treated surgically:

suppress cortisol to <50 nmol/L after giving 0.5 mg of

Transphenoidal surgery (in most cases)

dexamethasone 6 hourly for 2 days, suggests the diag-

Transcranial surgery (rarely, in very large tumours)

nosis of Cushing’s syndrome

• Pituitary hormone deficiency should be treated by

Suppression of cortisol to >50% of basal levels after

hormone replacement (pituitary failure is usually associ-

giving 2 mg of dexamethasone 6 hourly for 2 days

ated with multiple hormonal deficiencies)

suggest pituitary cause (i.e. Cushing’s disease)

The main tests for pituitary function are summarized

Clinical disease of the anterior

in Table 1.

pituitary gland

This section discusses the effects of over- and underpro-

Imaging of the pituitary gland

duction of a particular hormone.

Magnetic resonance imaging (MRI)

• This is the gold standard for imaging of the pituitary

Abnormalities of growth hormone secretion

gland (Fig. 4 shows a pituitary adenoma that enhances

Growth hormone excess

after godalinium injection)

In childhood or adolescence growth hormone excess

results in:

Combination of imaging with stimulation tests

• Excessive growth spurt

• In some complicated cases it may be necessary to

• Increased size of feet and hands

perform inferior petrosal sinus sampling under radio-

• General skeletal enlargement

logical guidance followed by stimulation tests

• Increased skin thickness

The pituitary gland

Thickening of lips and tongue

Dental malocclusion and widely spaced teeth

• Wide and large hands/feet (enlargement of soft tissue,

skin and cartilage), typically presenting with

Increasing glove size

Tight-fitting rings

Increasing shoe size

• Deep voice

• Nerve entrapment: carpal tunnel syndrome is not

uncommon (soft tissue enlargement)

• Increased sweating (common complaint)

• Organomegaly

Goitre

Cardiomegaly

Hepatomegaly

Splenomegaly

(a)

• Complications of acromegaly include (may be the

presenting feature of the disease):

Hypertension

Diabetes

Obstructive sleep apnoea

Increased risk of heart disease

Increased risk of colonic polyps and colonic

carcinoma

Investigations

• Random GH

A random GH of <1 mIU/L makes the diagnosis of

acromegaly unlikely

A random GH >1 mIU/L does not help in making a

diagnosis

• Glucose tolerance test

Failure of GH suppression after GTT suggests the

diagnosis of acromegaly

• Insulin-like growth factor-1 (IGF-1) levels

(b)

These are elevated in acromegaly but this is mainly

Figure 4 MRI of the pituitary showing a pituitary adenoma,

used to monitor response to therapy

before (a) and after (b) gadolinium injection.

• Imaging

• If left untreated, growth hormone excess in this period

Pituitary MRI: this usually shows a pituitary tumour

of life leads to gigantism, the most serious consequence

of the disease

Treatment

In adults, growth hormone excess affects the skin, soft

• Transphenoidal surgery: the treatment of choice

tissue and skeleton resulting in acromegaly, which has the

• Radiotherapy: in patients with failed surgery or if

following features:

surgery is contraindicated

• Acromegalic face (coarse facial features, see Fig. 5,

• Medical treatment

colour plate section)

Somatostatin analogues: used in patients with

Prominent supraorbital ridges

residual tumour post surgery or in whom surgery is

Large nose

contraindicated. It is effective at reducing GH levels in

Lower jaw pushed forward (prognathism)

around 60% of patients

Part 1: Basics

Dopamine agonists (cabergoline, bromocriptine):

Table 2 Main symptoms, signs and complications of growth

effective in a minority of patients

hormone excess and deficiency.

Pegvisomant: relatively new and effective treatment

Growth hormone excess

Growth hormone deficiency

that blocks the growth hormone receptor but has no

effect on growth hormone levels. The effect of this

Symptoms

treatment on tumour size remains controversial

Fast growth (in children)

Failure of growth (in children)

• Monitoring response to treatment

GH day curve: mean GH <5 mIU/L defines cure

Headaches (independent of

Tiredness

local tumour effect)

from the disease

Depression

IGF-1 levels: the aim is to normalize IGF-1 levels

Increased sweating

Decreased body mass

Due to increased risk of colonic cancer, acromegaly

Musculoskeletal pains

patients should undergo regular colonoscopy for early

detection of the disease

Change in glove/ring and

shoe size

Growth hormone deficiency

Signs

In childhood, growth hormone deficiency (GHD) results

Facial appearance (see text)

Failure of growth and thin

in:

skin in children

Soft tissue and skeletal

• Failure of growth

changes

No specific signs in adults

• Thin skin

Organomegaly

• Hypoglycaemia (particularly in the presence of ACTH

deficiency)

Visual field defect

• Delayed puberty (particularly in the presence of sex

Deficiency of other pituitary

hormone deficiency)

hormones

In adults, GHD results in non-specific symptoms:

Complications

• Tiredness

Hypertension

Short stature in untreated

• Depression

children

• Reduction in muscle and increase in fat mass

Diabetes

The main clinical features of growth hormone excess/

Hypoglycaemia (mainly in

Colonic polyps and colonic

deficiency are summarized in Table 2.

children)

carcinoma

Osteoporosis in adults

Obstructive sleep apnoea

Investigations

• Glucagon stimulation test or insulin stress tests

Failure of GH to rise after these stimulation tests

suggests GHD

Abnormalities of ACTH secretion

• IGF-1 levels

ACTH excess

Low IGF-1 aids in the diagnosis. However, normal

Pituitary tumours producing ACTH result in excessive

IGF-1 levels do not rule out the possibility of GHD

cortisol production by the adrenals, consequently leading

• Imaging

to pituitary-dependent Cushing’s syndrome (or Cush-

Pituitary MRI should be performed in subjects

ing’s disease), which must be differentiated from other

with GHD to rule out the possibility of pituitary

causes of Cushing’s syndrome, including:

tumour causing GHD by compressing GH-producing

• Ectopic ACTH syndrome: due to the presence of

cells

malignant cells producing ACTH

(lung cancer for

example)

Treatment

• Adrenal tumours: excess cortisol production is associ-

• Childhood GHD

ated with suppression of ACTH production and, there-

GH replacement is necessary

fore, these tumours are usually referred to as non-ACTH

• Adult GHD

dependent Cushing’s syndrome

Only symptomatic patients are usually offered GH

• Pseudo-Cushing’s: excessive alcohol consumption or

replacement therapy

severe depression can result in symptoms and signs

The pituitary gland

similar to Cushing’s syndrome, and differentiating this

from “real” Cushing’s can sometimes be difficult even for

Red cheeks

an experienced endocrinologist

Moon face

Fat pads

Box 1 Clinical features of Cushing’s syndrome

Bruisabillity

with ecchymoses

• Growth arrest in children

• Typical facial appearance (see Fig. 6)

Striae

Round (moon-like) face

Acne

Pendulous

Thin skin

Hirsutism

abdomen

Thinning of scalp hair

• Fat redistribution

Truncal obesity

Proximal

Thin extremities

myopathy

Supraclavicular fat pads

• Skin abnormalities

Thin skin

Poor wound

Striae on abdomen, breast and axillae (due to central

healing

obesity and thinning of the skin)

• Mood problems

Depression

Psychosis

Figure 6 Typical facial appearance of Cushing’s disease.

Insomnia

• Sexual dysfunction

Low libido and impotence

Menstrual problems

• Complications

doses) and check cortisol levels thereafter, which

Hypertension

should be undetectable in the absence of Cushing’s

Diabetes mellitus

syndrome

Osteoporosis

• Differentiate between different causes of Cushing’s

High risk of infections

syndrome

Poor wound healing

ACTH levels: these are suppressed in adrenal Cush-

ing’s but detectable in pituitary Cushing’s disease or

Investigations

cases due to ectopic ACTH production

• Confirm the presence of excess cortisol

High dose dexamethasone suppression test: give

24-hour urinary cortisol: high levels are suggestive

2 mg dexamethasone every 6 h for 2 days. If cortisol is

of Cushing’s syndrome

suppressed to more than 50% of basal value, it suggests

Midnight cortisol: in normal individuals, cortisol

a diagnosis of pituitary Cushing’s disease

levels at midnight during sleep are undetectable. This

• Imaging

test may be difficult to arrange as the patient needs to

MRI of the pituitary: may show a pituitary tumour

be admitted and a blood sample should be taken

but it can sometimes be normal (tumour too small to

immediately after the patient is woken up

visualize)

Overnight dexamethasone suppression test: give

Petrosal sinus sampling: this may need to be under-

0.5-1.0 mg of dexamethasone at 23:00 and measure

taken in difficult cases to differentiate ectopic ACTH

cortisol at 09:00. Cortisol levels less than 50 nmol/L

secretion from pituitary-dependent Cushing’s disease

effectively rule out the diagnosis of Cushing’s

syndrome

Treatment of Cushing’s disease

Low dose dexamethasone suppression test: give

• Transphenoidal surgery to remove the pituitary

0.5 mg dexamethasone ever 6 hours for 2 days (eight

tumour

Part 1: Basics

• Radiotherapy: in relapsed disease or in those whom

Table 3 Main symptoms, signs and complications of ACTH

surgery is contraindicated

excess and deficiency.

• Adrenalectomy: in difficult cases

(to stop cortisol

ACTH excess

ACTH deficiency

secretion), but this is rarely performed

Symptoms

ACTH deficiency

Failure of growth (in children)

This results in the failure of cortisol production by the

Weight gain

General malaise and weakness

adrenal glands. This results in:

• Failure of growth in children

Thin skin and easy bruising

Dizziness

• Malaise and tiredness

Muscle weakness

Generalized aches and pains

• Weight loss

Mood disturbances

Abdominal pain, diarrhoea

• Hypoglycaemia

and vomiting

• Hypotension

Reduced libido and menstrual

• Confusion

irregularities

Reduced libido and menstrual

The main clinical features of ACTH excess/deficiency are

irregularities

summarized in Table 3.

Signs

Facial appearance (see text)

Postural hypotension

Investigations

Truncal obesity, buffalo hump

Decreased axillary and pubic

• Pituitary stimulation tests (insulin stress test or gluca-

hair

Thin and fragile skin

gons stimulation test) fail to show adequate rise in serum

cortisol levels

Abdominal and axillary striae

• The possibility of primary hypoadrenalism should be

Increased pigmentation due

ruled out, in which case there is:

to high ACTH (skin and

Low cortisol

mucous membranes)

High ACTH

Proximal muscle weakness

• ACTH deficiency is usually part of panhypopituitarism

and, therefore, deficiency of other hormones should be

Visual field defect

investigated

Deficiency of other pituitary

• In subjects with pure ACTH deficiency a CRH test may

hormones

be necessary to confirm the diagnosis (failure of ACTH

Complications

and cortisol to rise confirm ACTH deficiency)

Hypertension

Hypoglycaemia

• Imaging

Pituitary MRI to investigate the possibility of

Diabetes

Death

pituitary tumour

Osteoporosis

Infections

Treatment

• Cortisol replacement is necessary and usually oral

hydrocortisone is used in two to three divided doses

• Causes of raised plasma prolactin concentration

seem to be a popular question in postgraduate medical

Abnormalities of prolactin secretion

examinations

Prolactin excess

• Prolactinomas are the commonest functioning

Clinical presentation

pituitary tumours

Prolactinomas result in:

• Microprolactinomas are detected in up to 10% of the

• Galactorrhoea (90% of women and 15% of men)

population in post-mortem studies

• Sexual dysfunction

• Serum prolactin concentration may be elevated due to

• Decreased libido

a large number of factors (summarized in Table 4), which

• Menstrual irregularities

should be differentiated from a prolactinoma.

• Local tumour effects

The pituitary gland

Table 4 Causes of high plasma prolactin levels.

Treatment

• Pituitary prolactinomas are usually treated medically

Physiological

Pregnancy

with dopamine agonists (cabergoline or bromocriptine),

Nipple stimulation

which result in both reduced hormone secretion and

shrinkage of the tumour

Sexual intercourse

• Surgery is reserved for severe cases that are not

Stress (simple venepuncture may cause PRL

responding to medical treatment (and these are fortu-

elevation)

nately rare)

Pituitary

Prolactinoma

• It should be noted that prolactinomas are the only

tumours

pituitary tumours where medical therapy, rather than

Non-functioning tumours (elevation of

surgery, is first-line treatment and, therefore, it is impor-

prolactin is usually modest due to stalk

tant to make the correct diagnosis in these cases

compression and lack of inhibition of

prolactin secretion)

Drugs

Large list including:

Prolactin deficiency

• Deficiency of prolactin results in failure of lactation in

Anti-emetics

women with no other systemic effects

Antidepressants and antipsychotics

• This is usually part of other pituitary hormonal

deficiency

Opiates

• Can result from severe blood loss during childbirth,

Anti-HIV treatment

resulting in pituitary infarction, which is called Sheehan’s

Hypothalamic

Tumours compressing the hypothalamus

syndrome

disease

• There is no prolactin replacement therapy and defi-

Infiltrative disease (sarcoidosis)

ciency of this hormone is not treated

Large pituitary tumours causing stalk

compression

Abnormalities in TSH secretion

Metabolic

Hypothyroidism

TSH excess

Chronic renal disease

TSH excess is rare and is usually due to a pituitary tumour

(TSH-oma). It results in:

• Features of hyperthyroidism (clinical presentation is

discussed in the chapter on the thyroid)

• Mass effect of the pituitary tumour (particularly as

Investigations

these tumours tend to be large)

• Raised serum prolactin is suggestive of the diagnosis,

provided other causes for raised prolactin are ruled out

Investigations

(see Table 4)

• High FT4 with high or normal TSH in subjects not on

• Imaging

thyroxine replacement is suggestive of TSH-producing

MRI of the pituitary usually shows a pituitary

pituitary tumour

tumour, particularly in those with very high prolactin

• Imaging

levels

MRI of the pituitary: this usually shows a large

In some patients no tumour can be identified but

tumour

this does not rule out the diagnosis of prolactinoma

(tumour can be too small)

In patients with a large pituitary tumour and only

Treatment

mild elevation of prolactin, a non-functioning

• Transphenoidal surgery

pituitary adenoma rather than a prolactinoma should

• Somatostatin analogues for recurrent or incompletely

be suspected (raised prolactin in this case is due to stalk

removed tumours

compression and ‘escape’ from the inhibitory effects of

• Radiotherapy in case of recurrent tumour or unsuc-

hypothalamus)

cessful surgery

Part 1: Basics

TSH deficiency

Treatment

TSH deficiency causes hypothyroidism (usually associ-

• Treat the underlying cause

ated with other pituitary hormone deficiency).

• Sex hormone replacement

The clinical features of hypothyroidism are discussed

Testosterone

in the chapter on the thyroid.

Oestrogen and progesterone

Investigations

Non-functioning pituitary adenoma

Low FT4 with low or normal TSH is suggestive of TSH

These are the commonest of pituitary macroadenomas.

deficiency and the pituitary gland should be fully evalu-

They present clinically with:

ated for deficiencies of other pituitary hormones.

• Mass effect

• Visual field defect

Treatment

• Headaches

• Thyroid hormone replacement in the form of synthetic

• Cranial nerve palsies

T4 (levothyroxine)

• Hypopituitarism: resulting in GH, ACTH, TSH and

• It should be noted that TSH measurements cannot be

gonadotrophin deficiencies (variable degrees), with the

relied upon for monitoring the thyroxine dose, which is

clinical manifestations described above

simply done by measuring FT4 levels and assessing the

patient clinically

Investigations

• In patients with combined ACTH and TSH deficiency,

Static pituitary function tests

cortisol therapy should be started first and thryoxine

• TFTs

replacement introduced a few days later to avoid precipi-

• Sex hormones and gonadotrophin levels

tating an adrenal crisis

• Prolactin (may be mildly elevated in non-functioning

tumours; see section on prolactinoma)

Abnormalities of gonadotrophin secretion

Gonadotrophin excess

Stimulation tests

Tumours producing FSH or LH are extremely rare and

• Insulin stress test or glucagon stimulation test to

usually behave similarly to a non-functioning pituitary

assess:

tumour. In men, FSH-secreting tumours may result in

Cortisol (ACTH) reserve

testicular enlargement.

GH reserve

• Suppression tests: only if there is a clinical suspicion

Gonadotrophin deficiency

of:

This results in sex hormone deficiency.

Clinical presentation

Box 2 Pituitary tumours

• Decreased libido, impotence and menstrual

irregularities

Pituitary tumours may be:

• Loss of secondary sexual hair

• Functional, secreting one or more hormones resulting in:

• Loss of muscle mass in men

Galactorrhoea (prolactin)

• In children

Acromegaly (GH)

Delayed puberty and sexual infantilism

Cushing’s syndrome (ACTH)

Hyperthyroidism (TSH)

Primary amenorrhoea

• Non-functional, causing:

Mass effect

Investigations

Anterior pituitary failure: this can be partial (one or

• Low testosterone in men and oestradiol in women with

two hormones) or total (involving all pituitary

low or normal gonadotrophin levels, suggest secondary

hormones)

gonadal failure

Suspected pituitary tumours should be investigated with

• Imaging

hormonal tests (rule out hyper- and hyposecretion of

Pituitary MRI should be performed in subjects with

hormones) as well as imaging tests

secondary gonadal failure

The pituitary gland

Cushing’s syndrome

Table 5 Causes of syndrome of inappropriate ADH (SIADH)

Acromegaly

secretion.

• Imaging

Tumours

Cancers: Lung malignancy, haematological

Pituitary MRI: shows a pituitary macroadenoma

malignancies, etc.

Treatment

Central nervous

Infection (meningitis, encephalitis)

• Surgery: usually transphenoidal but transcranial

system

Head injury

surgery may be needed for larger tumours

abnormalities

Vascular disorders

• Radiotherapy: for recurrence

• Hormone replacement therapy: these patients usually

Respiratory

Infections

end up with a mixture of pituitary hormonal deficiencies,

abnormalities

Positive pressure ventilation

which should be replaced

Drugs

Chemotherapy

Anti-epileptic (carbamazepine)

Box 3 Other causes of pituitary failure

Oral hypoglycaemic (chlorpropamide)

• Pituitary infarction, characterized by:

Antipsychotics

Sudden onset headache

Endocrine

Hypothyroidism

Cranial nerve palsies

Symptoms and signs of cortisol deficiency

Metabolic

Acute intermittent porphyria

• Pituitary infiltration

Idiopathic

All above causes need ruling out before

Sarcoidosis

making this diagnosis

Haemochromatosis

• Trauma

• Pituitary infection

Abscess

Tuberculosis

Abnormalities of ADH secretion

• Head irradiation

• Arginine-vasopressin or antidiuretic hormone

• Unknown causes

This hormone is secreted secondary to osmotic

Treatment of pituitary failure includes one or a cocktail

changes

of hormone replacement therapies:

Mediates free water reabsorption in the kidneys

• Steroids (hydrocortisone): anyone with suspected

pituitary failure should be given hydrocortisone and

Excessive ADH secretion - syndrome of

investigated later (failure to give hydrocortisone in

inappropriate ADH secretion (SIADH)

suspected deficiency may result in death)

• Thyroxine: should only be given after adequate cortisol

This is not uncommonly seen on the medical wards and

replacement

results in:

• Testosterone (males), oestrogen and progesterone

• Dilutional hyponatraemia

(females)

• Low plasma osmolarity and inappropriately high urine

• Growth hormone: this is routinely given to children with

osmolarity

(secondary to water reabsorption in the

GH deficiency but in adults, only those with symptoms

kidneys)

receive this expensive form of treatment

• Causes of inappropriate ADH secretion (known as

syndrome of inappropriate ADH or SIADH) are sum-

marized in Table 5.

The posterior pituitary

In contrast to the anterior pituitary, the posterior pitu-

Investigations

itary does not synthesize hormones but stores hormones

• Hyponatraemia is commonly seen in hospitalized

produced in the hypothalamic region. These hormones

patients. A common ‘knee jerk reaction’ is to label these

include:

patients as having SIADH and start fluid restriction,

• Antidiuretic hormone (ADH)

which can be detrimental if the patient is not assessed

• Oxytocin

properly

Part 1: Basics

• It should be remembered that patients with SIADH are

Functional ADH deficiency may occur if the kidneys

euvolemic and therefore:

fail to respond to the hormone (ADH production is

It is important to rule out dehydration before start-

normal). This is called nephrogenic DI, which may be:

ing investigations for SIADH (are they on diuretics? is

• Congenital or familial

there a history of recent fluid loss?)

• Acquired

It is also important to rule out fluid overload before

Drugs (lithium or demeclocycline)

starting investigations for SIADH (is there advanced

Electrolyte abnormalities: hypercalcaemia, hypo-

heart, liver or renal failure?)

kalaemia

• In euvolemic patients, SIADH should be suspected in

Chronic renal disease

the presence of:

Hyponatraemia with low plasma osmolarity

Box 4 Abnormalities of oxytocin secretion

Inappropriately high urine osmolarity

High urinary sodium excretion

In women, oxytocin:

• In patients with suspected SIADH, we need to exclude:

• Helps contraction of the pregnant uterus

Hypothyroidism (TFTs)

• Helps contraction of breast duct smooth muscle aiding

breast feeding

Hypoadrenalism (short synacthen test)

• Deficiency of this hormone has no effect on parturition

• Once the diagnosis of SIADH is made, it is necessary

or breast feeding

to establish the cause (see Table 5)

In men, the role of this hormone is unclear

Careful history and examination of the patient

Double check drug history

Computed tomography

(CT) head, chest and

Special cases in pituitary disease

abdomen are frequently requested to rule out a

What is pituitary apoplexy?

malignant cause

• This is caused by infarction of the pituitary gland, con-

sequently resulting in failure of hormone production

Treatment

• Can occur in patients with large pituitary tumours

In confirmed SIADH:

• Any individual with known or suspected pituitary

• Restrict oral fluid to 750-1500 mL of oral fluid/day

tumour complaining of sudden onset severe headache

• Treat the cause

with or without cranial nerve palsies (III, IV and VI)

• Demeclocycline, which induces nephrogenic diabetes

should be suspected as having pituitary apoplexy

insipidus, can help in difficult cases

• Urgent MRI of the pituitary should be requested

ADH deficiency

• These patients should be given parenteral steroids

This results in the passage of large volume of dilute urine,

What is a craniopharyngioma?

resulting in:

• A tumour arising from the epithelial remnants of

• Polyuria

Rathke’s pouch

• Nocturia

• Can be present at any age and half the subjects are

• Thirst

children

• Enuresis in children

• Clinical presentation is similar to a non-functioning

Causes of ADH deficiency, also known as cranial

pituitary adenoma

diabetes insipidus (DI) are:

• The presence of calcification in a pituitary tumour

• Congenital or familial

should raise the suspicion of a craniopharyngioma

• Acquired

• Treated surgically but recurrence rates are high

Head injury

What is lymphocytic hypophysitis?

Tumours infiltrating the posterior pituitary

• A rare inflammatory condition of the pituitary, likely

Infiltrative conditions, such as sarcoidosis or

to be autoimmune in origin

histiocytosis

• Results in pituitary hormonal failure and can cause a

Infections such as meningitis, encephalitis or

mass effect

tuberculosis

• Spontaneous recovery may occur

Vascular

• Usually treated with replacement of deficient

Idiopathic

hormone(s)

The thyroid

Anatomy

Pathophysiology of the thyroid

• The thyroid is composed of a midline isthmus just

Disorders of the thyroid gland include:

below the cricoid cartilage (Fig. 7), a right and a left lobe,

• Hormonal hypersecretion (hyperthyroidism): with or

extending from the isthmus laterally

without thyroid gland enlargement (thyroid goitre)

• Thyroid cells are arranged in follicles and produce

• Hormonal hyposecretion (hypothyroidism): with or

thyroid hormones, which are stored in the lumen of the

without thyroid goitre

follicle

• Thyroid nodules/goitre with normal thyroid hormone

• The thyroid also contains C cells, which produce

levels

calcitonin

• Thyroid cancers

Physiology

An approach to a patient with suspected

• Iodine is an essential component of thyroid

thyroid disease

hormones

A proper history is important particularly in relation

• The thyroid gland traps iodine from the plasma, a

to:

process mediated by the sodium iodide symporter

• Symptoms of hyper- or hypothyroidism (see below)

• Iodine is then organified and iodothyronines (thyroid

• In the case of thyroid nodules or goitre:

hormones) are formed, a process mediated by the enzyme

Recent change in size

thyroid peroxidase (TPO)

Recent hoarse voice

• Thyroid hormones are stored in thyroid follicles bound

Compressive symptoms (difficulty in breathing or

to thyroglobulin (TG)

swallowing)

• In response to demand, TG is internalized by thyroid

follicular cells, and thyroid hormones are liberated into

the blood stream

• Thyroid hormone secretion is constituted of 20% T3

Box 5 Examination of the thyroid

and 80% T4

• T4 is converted in peripheral tissue to the active

Assessment of thyroid status

hormone T3, through the action of deiodinase enzymes

• General

• Thyroid hormones are bound to plasma proteins (thy-

Is the patient fidgety or agitated?

roxine binding globulin, albumin) and their levels can be

Facial appearances

influenced by plasma protein concentrations. Therefore,

Is the patient’s clothing appropriate? (Wearing a

free thyroid hormone levels should be measured in cases

t-shirt in December suggests hyperthyroidism!)

• Hand tremor: best checked by placing a piece of paper

of suspected thyroid hormone abnormalities

on outstretched arms

• Thyroid hormone production is regulated by the

• Sweaty or dry skin (check palms)

hypothalamus and pituitary gland as shown in Fig. 8.

• Feel pulse (tachycardia, atrial fibrillation or bradycardia)

• Assess for lid lag

• Check for signs of proximal myopathy

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

• Tendon reflexes (ask the patient to kneel on a chair and

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

check ankle reflexes)

Part 1: Basics

Hypothlamus

Superior

thyroid artery

Larynx

Thyroid gland

TRH

Common

Isthmus

carotid

Pituitary

artery

Inferior thyroid

artery

Trachea

TSH

Figure 7 Anatomy of the thyroid gland. The isthmus of the

gland thyroid is located just below the cricoid cartilage. The

right and left lobes extend laterally and some individuals have

Thyroid

a small conical lobe extending from the isthmus upwards

called the pyramidal lobe.

Assessment of the thyroid gland

• Inspection

Observe for any neck swelling; ask the patient to swallow

Thyroid Hormones

and observe for a neck mass that moves with swallowing

(T3 and T4)

A midline structure moving by tongue protrusion

suggests a thyroglossal cyst

Figure 8 Regulation of thyroid hormone production. The

• Palpation

hypothalamus produces thyrotropin releasing hormone (TRH),

Palpate the thyroid starting in the isthmus and moving

which stimulates the pituitary to secrete thyroid stimulating

out laterally and upwards. Use the pulp not the tip of

your fingers

hormone (TSH), which in turn stimulates the thyroid gland to

Feel the neck for lymphadenopathy

synthesize and release thyroid hormones. T3 and T4 have a

• Percussion: gives limited information about the possibility

negative feedback effect on TRH and TSH production.

of retrosternal extension of a goitre

• Auscultation: bruit over the thyroid gland suggest a

diagnosis of Graves’ disease (due to increased gland

Hyperthyroidism

vascularity)

Causes of hyperthyroidism are summarized in Table 6.

• Check for Pemberton’s sign: raising both arms above the

head results in venous obstruction, which can be seen in

Graves’ disease (GD)

large goitres with retrosternal extension

• The commonest cause of hyperthyroidism (80% of

Assessment for signs of extrathyroidal disease (in

cases)

suspected Graves’ disease)

• An autoimmune condition characterized by the pres-

• Graves’ ophthalmopathy

Proptosis

ence of thyroid stimulating antibodies (TSAb), mimick-

Periorbital oedema

ing the action of TSH and resulting in hyperthyroidism

Conjunctival injection

• Can be associated with extrathyroidal manifestations

Chemosis

(summarized in Table 7, Fig. 9, colour plate section)

Corneal ulceration

Inability to fully close the eyes

Clinical presentation

• Pretibial myxoedema

• Patient usually presents with classical symptoms

• Thyroid acropachy

hyperthyroidism (summarized in Table 8)

The thyroid

Table 6 Causes, aetiology and diagnosis of hyperthyroidism.

Cause of hyperthyroidism

Frequency and aetiology

Diagnosis

Graves’ disease

80%, thyroid stimulating antibodies

Clinical examination

Thyroid autoantibodies

Thyroid uptake scan in uncertain cases

Toxic nodule or toxic

15%, activating mutations in TSH receptor

Clinical examination

multinodular goitre

and Gsα protein

Thyroid uptake scan

Thyroiditis

2-4%, autoimmune, viral or drug-related

Clinical examination

(amiodarone)

Thyroid uptake scan

ESR

TSH-secreting tumour

<1%

Raised TSH and thyroid hormones; pituitary imaging

Exogenous thyroid hormone

Variable, excess ingestion of thyroid

Clinical assessment

administration

hormones

Hyperemesis gravidarum

Rare, raised hCG (mimicking TSH action)

Clinical assessment

Choriocarcinoma

Absence of thyroid autoimmunity

Known pregnancy

Imaging of the pelvis

Struma ovarii

Rare, ectopic ovarian thyroid tissue

Clinical assessment

Thyroid/pelvic uptake scan

Imaging of the pelvis

Thyroid hormone resistance

Rare, pituitary resistance to thyroid

Clinical assessment

hormones

Family history

ESR, erythrocyte sedimentation rate; hCG, human chorionic gonadotrophins.

• Neck palpation reveals a smooth, uniform goitre in the

Thyroid uptake scan: in Graves’ disease this shows

majority of cases

uniform uptake of technetium or iodine (Fig. 10)

• Around half the patients will have extrathyroidal man-

ifestations of the disease (summarized in Table 7 and

Treatment

shown in Fig. 9 and Fig. 40)

GD can be treated with antithyroid drugs, radioactive

iodine and surgery. Symptomatic treatment is also

Investigations

possible in patients with severe symptoms; β-adrenergic

• Confirm the presence of hyperthyroidism:

blocking agents (propranolol) can be used but these are

Suppressed TSH

only required in a minority.

Raised thyroid hormones (T4 and/or T3)

Detection of thyroid stimulating antibodies: not

essential for making the diagnosis and usually reserved

Antithyroid drugs (thionamides)

for atypical cases. These are positive in 95-99% of GD

• Include propylthiouracil, carbimazole and its active

cases depending on the type of assay used

metabolite methimazole

• In uncertain cases (no or asymmetrical goitre, negative

• These agents interfere with the action of thyroid peroxi-

antibodies):

dase, thereby inhibiting thyroid hormone production

Part 1: Basics

Table 7 Extrathyroidal manifestations of Graves’ disease.

Table 8 Symptoms and signs of Graves’ disease.

Extrathyroidal disease, usually Graves’ ophthalmopathy (GO)

Hyperthyroidism due to other causes presents with similar

can be seen even in individuals with normal thyroid function.

symptoms and signs except for the absence of GO, PTM and

acropachy.

Extrathyroidal

Clinical findings

manifestations of

Symptoms

Frequency

Graves’ disease

Nervousness, heat intolerance and perspiration,

85-95%

Graves’

Clinically evident in 50% of Graves’

palpitations, fatigue

ophthalmopathy

disease patients but can be seen in 90%

Increased frequency of stools, weight loss with

75-85%

using imaging techniques

increased appetite

Characterized by swelling of the

Symptoms of Graves’ ophthalmopathy

50%

extraorbital muscles and proliferation of

adipose and connective tissue in the

Insomnia, polyuria and menstrual irregularities

20-30%

orbit

Signs

Frequency

The above results in proptosis of the

eyes and in severe cases exposure

Hyperkinetic behaviour, tachycardia or atrial

90-95%

keratitis. Also, it may result in

fibrillation

ophthalmoplegia and optic neuropathy

Goitre, warm and moist skin, hand tremor

90%

Graves’ dermopathy

Rare, usually affects the shins (hence

pretibial myxoedema)

Signs of Graves’ ophthalmopathy

50%

Skin looks discoloured, indurated and

Pretibial myxoedema

can be itchy

Onycholysis, acropachy

<5%

Graves’ dermopathy is almost always

Rare presentations

associated with GO

Thyroid storm: an extreme form of thyrotoxicosis presenting

Graves’ acropachy

Very rare, usually associated with GO

with fever, cardiovascular collapse, confusion, psychosis, severe

and Graves’ dermopathy

weakness and even coma. This is a life-threatening emergency

that requires urgent medical treatment (see text).

Characterized by clubbing and

subperiostal new bone formation

Apathetic hyperthyroidism: the adrenergic hyperactivity

manifestations are absent and this presentation can be confused

with depression (usually occurs in the elderly).

• Antithyroid drugs can be given as

Titration regime (usually for 18 months): enough

antithyroid drug is given to keep the thyroid hormones

in the normal range

Box 6 Side effects of antithyroid drugs

Block and replace regime (usually for 6 months): a

large dose of antithyroid drug is given to fully block

• Agranulocytosis: the most serious complication and all

patients are advised to immediately report to their

thyroid hormone production and thyroxine replace-

physician in case they develop a temperature, sore

ment therapy is added to ensure adequate plasma

throat or mouth ulcers. Agranulocytosis with either

thyroid hormone levels

propylthiouracil or carbimazole represents a

After 6-18 months, treatment is stopped and disease

contraindication to the use of these agents

remission is achieved in less than 50%

• Minor side effects such as rash, musculoskeletal pain,

deranged liver function. If these occur, it is possible to

Radioactive iodine (RAI)

switch between antithyroid drugs

• Safe and effective treatment (up to 90% respond after

one dose)

• Used as second line in Europe but frequently as first

• RAI treatment destroys the thyroid gland and can take

line in America

up to 6 months to have full effect

The thyroid

Surgery

This is reserved for those with:

• Large goitre

• Personal preference

• Severe hyperthyroidism and intolerance to antithyroid

drugs

Toxic solitary nodule (TN) and toxic

multinodular goitre (TMNG)

Around 15% of hyperthyroid patients have a TN or

TMNG.

Clinical presentation

• Symptoms and signs of hyperthyroidism

• Neck palpation reveals an irregular goitre or a thyroid

nodule

(a)

• There are no extrathyroidal signs

Investigations

• Confirm the presence of biochemical hyper-

thyroidism

• Thyroid uptake scan shows one or more thyroid

nodules with increased uptake, which are often referred

to as “hot” nodules

• Hyperthyroidism due to toxic nodule(s) must be dif-

ferentiated from GD and a cold nodule (an uptake scan

can be used), due to the relatively high prevalence of

malignancy in GD-associated cold nodules

• A thyroid uptake scan for a toxic nodule is shown in

(Fig. 11)

Treatment

• Toxic solitary nodule or toxic multinodular goitre can

be treated with antithyroid drugs but the disease relapses

(b)

once medical treatment is stopped

Figure 10 Technetium scan in an individual with Graves’

• The best treatment option is radioactive iodine, which

disease, demonstrating uniform uptake and thyroiditis

often restores euthyroidism

showing lack of uptake. Courtesy of Dr R. Bury, the

• Surgery is also an option but is reserved for a minority

Radionuclide Department, University of Leeds.

of patients, usually those with large disfiguring goitres

• Fine needle aspiration

(FNA) is only required in

selected cases (malignancy in toxic nodules is rare) and

• Induces long-term hypothyroidism (patients need to

this is discussed below

be warned that they will potentially need lifelong treat-

ment with thyroxine)

• Contraindications include:

Thyroiditis

Absolute: pregnancy

• A relatively rare cause of hyperthyroidism

Relative: active eye disease (eye disease may worsen

• May be autoimmune in nature, follow a viral disease

after RAI)

or can be drug-related

Part 1: Basics

Table 9 Symptoms and signs of hypothyroidism.

Symptoms

Frequency

Weakness/lethargy, dry skin

95%

Sensation of cold and decreased sweating,

80%

oedema of the face

Impaired memory, constipation, hair loss and

65%

weight gain

Deafness and non-specific chest pain

30%

Signs

Frequency

Thick tongue, facial oedema, dry and cold skin

80%

Slow relaxing reflexes

75%

Bradycardia, skin pallor, coarse hair, depression

60%

Figure 11 Radioactive iodine uptake in a subject with

hyperthyroidism shows a toxic nodule with suppression of

uptake activity in the rest of the gland. Courtesy of Dr. R. Bury

the Radionuclide Department, University of Leeds.

• Thyrotoxic phase is usually followed by a hypothyroid

phase, which may require a short course of thyroid

Clinical presentation

hormone replacement until the thyroid follicular cells are

• Symptoms and signs of thyrotoxicosis as discussed

fully recovered

above

• Commonly secondary to a viral infection; therefore,

Hyperthyroidism secondary to TSH-secreting

thyrotoxic symptoms following a flu-like illness should

tumours (TSH-oma)

raise the suspicion of thyroiditis

• This is a rare cause of hyperthyroidism

• Individuals may experience pain and tenderness in

• It should be suspected in individuals with raised

the region of the thyroid gland, a condition called De

thyroid hormones and detectable TSH levels

Quervain thyroiditis

• TSH-oma is discussed in the pituitary section

• Diagnosis is made by demonstrating biochemical thyro-

toxicosis, associated with lack of uptake on thyroid scan

Hypothyroidism

(Fig. 10)

A common disease, mainly affecting the female popula-

• Postpartum thyroiditis

tion. Causes include:

Occurs in

5-10% of women within 1 year of

• Autoimmune hypothyroidism: by far the commonest

delivery

cause

Characterized by a hyperthyroid phase within 4-6

Atrophic (no goitre palpable)

months of delivery followed by a hypothyroid phase

Goitrous (Hashimoto’s thyroiditis)

with subsequent restoration of normal thyroid

• Postpartum thyroiditis

function

• Post-radiation

Permanent hypothyroidism eventually develops in

• Iodine deficiency

around one-third of patients

• Drugs (amiodarone, lithium)

Treatment

• Congenital developmental and biosynthetic defects

• The disease is self-limiting and treatment is not usually

• Secondary (due to pituitary or hypothalamic defects)

required

• For neck pain and tenderness, non-steroidal anti-

Clinical presentation

inflammatory agents can be used, whereas steroids are

This can be very variable and the commonest symptoms

reserved for severe cases

and signs are summarized in Table 9.

The thyroid

Investigations

• It may be due to:

• Biochemical testing shows low plasma thyroid hormone

Graves’ disease

levels with raised TSH

Toxic multinodular goitre

• Some individuals may have high TSH with normal

• Usually occurs in older individuals who may display

thyroid hormone levels, a condition known as subclinical

mild symptoms of hyperthyroidism but may be

hypothyroidism which is discussed below

asymptomatic

• Thyroid antibodies

(TPO antibodies) are usually

• Subjects with SHyper are at increased risk of:

detected

individuals

with

autoimmune

Atrial fibrillation

hypothyroidism

Osteoporosis

• Any subject with low plasma thyroid hormone levels

• Radioactive iodine is usually the best treatment option

with low or normal TSH should be suspected of having

for these individuals

secondary hypothyroidism (i.e. pituitary failure) and

urgent investigations/endocrine referral should be

Amiodarone-induced thyroid dysfunction

made

This can be a difficult condition to manage even for an

experienced endocrinologist. Amiodarone can result in

both hypo- and hyperthyroidism through:

Treatment

• High iodine content of the drug (40% of its weight)

• This is relatively simple and consists of replacing

• Direct toxic effect of amiodarone on thyroid follicular

thyroid hormone

cells

• L-thyroxine (T4) is usually given, which is converted

in the periphery to the active hormone T3

Amiodarone-induced hypothyroidism

• Combination therapy with T3 and T4 is very rarely

• Occurs in up to 15% of patients on the drug

used and only in selected patients who remain symptom-

• This can be simply managed by giving thyroid hormone

atic on T4 replacement alone

replacement similarly to individual with primary

• The appropriate dose of thyroxine should titrated to

hypothyroidism

suppress TSH below

2 mIU/L but full suppression

• Discontinuation of amiodarone (which is not always

should be avoided (usual replacement dose is around

possible) can result in restoration of normal thyroid

1.4 mcg/kg)

function

Special cases of abnormal thyroid function

Amiodarone-induced hyperthyroidism (AIT)

Subclinical hypothyroidism (SHypo)

This occurs in less than 5% of patients on amiodarone

• Raised TSH levels in the presence of normal thyroid

treatment, and can be divided into:

hormones is defined as SHypo

• AIT type I

• SHypo is usually due to early autoimmune

Similar to autoimmune hyperthyroidism

hypothyroidism

Can be managed with antithyroid drugs

• The term SHypo suggests the absence of symptoms but

RAI is usually ineffective (need to stop amiodarone

this is somewhat misleading as a large proportion of these

for a year before considering RAI)

patients are symptomatic

Thyroidectomy should be considered for difficult

• Thyroid function should be repeated within 3 months

cases

and if TSH remains elevated (or it is increasing), then

• AIT type II

treatment is advised, particularly in patients with positive

This is due to thyroiditis and thyroid destruction

TPO antibodies

Usually managed with high doses of steroids

• Some studies suggest an association between subclini-

• Mixed type I and type II AIT can occur and is best

cal hypothyroidism and atherosclerotic disease

managed by a combination of antithyroid drugs and

• The aim of treatment is to normalize TSH

steroids

• Amiodarone withdrawal is advisable in subjects with

Subclinical hyperthyroidism (SHyper)

AIT but this is not always possible

• Suppressed TSH with normal thyroid hormone levels

Any patient planned for amiodarone treatment should

(both T4 and T3) is defined as SHyper

have:

Part 1: Basics

Table 10 Important characteristics of type I and type II AIT.

The dose of thyroxine replacement is usually

increased in pregnancy by up to 50%

Type I AIT

Type II AIT

Thyroid hormone levels should be kept at the upper

end of normal (without TSH suppression) in women

Goitre

Frequent

Rare

with hypothyroidism receiving thyroxine replacement

Thyroid antibodies

Positive

Negative

during pregnancy

• Graves’ disease in pregnancy

Plasma CRP

Normal

High

Block and replace is contraindicated (antithyroid

Plasma IL-6

Normal

High

drugs cross the placenta whereas thyroxine does not,

Vascularity (Doppler studies)

Increased

Reduced

potentially resulting in fetal hypothyroidism)

• Propylthiouracil is probably safer to use than carbima-

CRP, C-reactive protein.

zole due to reported congenital abnormalities with the

latter

• Thyroid function and thyroid antibody screen done

• The lowest dose of antithyroid drugs should be used

prior to starting treatment

to keep thyroid hormones at the upper end of normal

• Thyroid function tested every 6 months whilst on this

range

therapy and for 12 months after discontinuing the drug

Table 10 summarizes the important characteristics of

Thyroid nodular disease in euthyroid subjects

type I and type II AIT.

(thyroid nodules and multinodular goitre)

• Very common, clinically evident in around 10% of the

Thyroid storm

UK population

A rare, severe and life-threatening case of hyperthyroid-

• A thyroid goitre can be physiological:

ism characterized by:

Puberty

• Reduced conscious level

Pregnancy

• Hyperthermia

• Non-physiological causes of thyroid goitre include:

• Multisystem decompensation (cardiac failure, renal

Thyroid autoimmunity

failure, etc.)

Iodine deficiency (endemic goitre)

Treatment consists of:

Drugs (lithium)

• High-dose antithyroid drugs

Other (unknown)

• Potassium iodine

• A thyroid nodule can be:

• β-blockers

Solid: composed of thyroid tissue

• Steroids

Cystic: usually filled with brown fluid

Mixed: solid/cystic

Myoedema coma

• Thyroid nodules/goitres are more common in

A rare, severe and life-threatening case of hypo-

women

thyroidism.

• Only a minority of thyroid nodules are malignant

• Often precipitated by infection

(<5%)

• Characterized by:

• Thyroid nodules are more likely to be malignant

Reduced conscious levels

in:

Hypothermia

Young (<20 years) or older (>60 years) subjects

Respiratory depression and associated CO₂

Rapidly growing nodule

retention

Compressive symptoms: hoarse voice, dysphagia,

• Treatment consists of:

breathing difficulties

T3 and T4

Family history of endocrine malignancy

Antibiotic cover after appropriate cultures

Cold nodule in an individual with Graves’ disease

Steroid cover

(associated adrenal dysfunction is

History of familial polyposis coli (papillary carci-

common)

noma), Hirshprung’s disease

(medullary thyroid

Hypo- and hyperthyroidism during pregnancy

cancer) or Hashimoto’s thyroiditis

(thyroid

• Hypothyroidism in pregnancy

lymphoma)

The thyroid

Table 11 Classification of thyroid cancers.

Characteristics

Papillary

Follicular

Anaplastic

Medullary* Lymphoma

Cell type

Thyroid cells

C cells

Lymphocytes

Age at presentation

30-50

40-50

>60

Any age

>40

Frequency

75%

15%

<5%

Prognosis

Good

Very poor

Variable

Treatment

Surgery and RAI ablation Surgery and RAI ablation Surgery

Surgery

Chemotherapy

radiation

Chemotherapy

External radiation

*May be part of MEN II or familial medullary carcinoma and is associated with raised serum calcitonin levels.

Clinical presentation

iodine ablation (high doses of radioactive iodine) if his-

Patient presents with a history of lump in the neck, which

tology confirms malignancy (up to 10% of FNA gives

is:

false-positive results)

• Observed by the patient

• Nodules with benign cytology can be followed up

• Observed by a family member/friend

medically with regular examination and repeat FNA as

• Detected during investigations for other pathologies

necessary

(ultrasound or CT neck)

Alarming features include:

Thyroid cancers

• Predisposition to thyroid malignancy as above

• Thyroid cancers are rare and mortality is low as most

• Rapidly growing goitre or nodule

carry a good prognosis

• Compressive symptoms or hoarse voice

• Occur more commonly in women but a thyroid nodule

• Very hard nodule

in man is more likely to be malignant

• Fixation of skin above the nodule

• Risk factors and indicators of malignancy in thyroid

• Presence of neck lymphadenopathy

nodules are discussed above

• Classification of thyroid cancers is summarized in

Investigations of thyroid nodules/multinodular

Table 11

goitre

• Fine needle aspiration (FNA) of the solitary nodule or

Clinical presentation

dominant nodule in a multinodular. A simple test, usually

• A thyroid nodule or goitre: a rapidly growing thyroid

done in a clinic

nodule should raise the suspicion of malignancy

Benign cytology: follow-up with repeat FNA in 6

• Post-mortem examination has shown that thyroid

months is required

cancers are not uncommon and individuals die with,

Inconclusive: repeat FNA (if repeat is undetermined

rather than from, the disease

then refer to surgery)

• Risk factors for thyroid cancers should be elicited in

Features of malignancy: surgery

the history

• CT scan in large goitres and in the presence of com-

• Hard nodules and cervical lymphadenopathy should

pressive symptoms

raise the suspicion of malignancy

• Pulmonary function tests to establish the presence of

respiratory compromise

Investigations

Treatment

• FNA as above

• Clinically and/or cytologically suspicious nodules

• Ensure that patient is not thyrotoxic before performing

should be treated with surgery, followed by radioactive

FNA

Part 1: Basics

Treatment

• Palliative radiotherapy can be arranged, whereas che-

Patients with cytologically proven papillary or follicular

motherapy is generally ineffective

thyroid malignancy should undergo:

Lymphoma

• Total thyroidectomy

• Usually treated with radio- and chemotherapy

• Radioactive iodine ablation

Patients with strong clinical suspicion of malignancy

• This should be followed by treatment with TSH-

but negative FNA should still be considered for surgery

suppressive doses of thyroxine (i.e. supraphysiological

as FNA can give false-negative results in a minority of

doses of throxine are given to keep TSH suppressed)

cases (5-10%).

Patients with medullary carcinoma should undergo:

Patients with previous thyroid cancer should be moni-

• Total thyroidectomy and lymph node dissection

tored for life

• Suppressive therapy with thyroxine is not needed

• Regular examination

(C cells are not controlled by TSH)

• Thyroglobulin plasma levels: detectable thyroglobulin

• Appropriate testing should be arranged to rule out

plasma levels after surgery and radioactive ablation

MEN II (see neuroendocrine section)

therapy indicate the presence of residual thyroid tissue

Anaplastic carcinoma

and, hence, recurrence of the disease

• Prognosis is very poor and surgery is rarely successful

Bone and calcium metabolism

Parathyroid hormone (PTH), secreted by the parathy-

from bone, increased intestinal absorption and reduced

roid glands, is the main hormone responsible for calcium

urinary excretion, and, hence, increases plasma calcium

haemostasis. There are five organs involved in calcium

levels (low blood calcium levels result in increased secre-

metabolism:

tion of PTH, whereas high levels lead to suppression of

• Parathyroid gland, through the secretion of PTH,

PTH release)

which increases plasma calcium levels

• Gastrointestinal tract: Vitamin D plays an important

• Gastrointestinal tract (absorption of calcium)

role in controlling absorption of calcium in the gut

• Renal tract (excretion of calcium)

Vitamin D undergoes

25-hydroxylation and

• Bone (storage of calcium)

hydroxylation in the liver and kidneys, respectively, to

• Thyroid gland, through the secretion of calcitonin by

form active vitamin D [1,25-(OH)₂D]

C cells

Vitamin D enhances intestinal calcium absorption

Calcitonin has a weak calcium-lowering effect

• Kidneys: calcium is reabsorbed by the kidneys, a

Plasma calcitonin levels are only used for the diag-

process regulated by PTH

nosis of medullary thyroid cancer and have no role in

• PTH results in increased calcium and decreased phos-

investigations of disorders of calcium metabolism

phate reabsorption (i.e. phosphate loss) by the kidneys.

Therefore, in primary hyperparathyroidism, hypercal-

Anatomy

caemia is often associated with hypophosphataemia

Usually, there are four parathyroid glands located at the

back of the thyroid gland (see Fig. 12). Rarely, ectopic

Pathophysiology

parathyroid tissue can be identified in the thoracic cavity,

• Hypocalcaemia and hypercalcaemia are relatively

which is due to abnormal parathyroid gland migration

common clinical conditions and are discussed below

during embryogenesis.

• Osteoporosis is characterized by an increase in osteo-

clast over osteoblast activity, resulting in reduction in

Physiology

bone mass (quantitative change), consequently predis-

Bones are in constant turnover, through the action of:

posing to fractures

• Osteoclasts: these cells are responsible for bone

• Osteomalacia is characterized by insufficient calcium

resorption

in bone tissue with normal bone mass

(qualitative

• Osteoblasts: these are responsible for bone formation

change)

Calcium is important for:

• In Paget’s disease, the activity of osteoblasts and osteo-

• Bone health

clasts is disorganized resulting in both bone resorption

• Neuromuscular conduction

and new bone formation in an uncoordinated manner

Plasma calcium levels, which should always be cor-

This chapter will discuss a number of different clinical

rected for plasma albumin, are kept in check by a number

entities including:

of mechanisms/organs:

• Hypocalcaemia

• Parathyroid gland: PTH results in calcium liberation

• Hypercalcaemia

• Osteomalacia and rickets

• Osteoporosis

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

• Paget’s disease

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

• Inherited bone abnormalities

Part 1: Basics

Clinical presentation

This can be variable from one person to another and is

related to the degree of hypocalcaemia. Symptoms

include:

Thyroid gland

• Tingling and numbness (often described by the patient

as pins and needles sensation) in the fingers, toes and

lips

Parathyroid gland

• Cramps

• In severe cases, stridor (due to spasm of laryngeal

muscles) and/or seizures

Low calcium results in neuromuscular irritability and,

Figure 12 The four parathyroid glands are located on the

therefore, the following signs can be found:

posterior aspect of the thyroid gland.

• Chvostek’s sign: tapping on the facial nerve in front

of the ear results in twitching of the corner of the

mouth

Hypocalcaemia

• Trousseau’s sign: inflation of the sphygmomanometer

This is not an uncommon condition and causes

above the arterial pressure results in carpopedal

include:

spasm

• Vitamin D deficiency: probably the commonest cause,

secondary to:

Investigations

Poor sunlight exposure (commonly seen in Asian

• Plasma calcium: diagnosis is confirmed by demon-

women who cover their bodies with clothes)

strating low plasma calcium (make sure corrected calcium

Malabsorption

(coeliac disease is a common

levels are assessed)

cause)

• Establish the cause:

Poor diet (frequently seen in the elderly)

Check PTH levels: low PTH levels in the presence of

Kidney disease (failure of 1-hydroxylation of vitamin

hypocalcaemia indicate parathyroid failure

Vitamin D levels: patients with low vitamin D levels

• Hypoparathyroidism

should be investigated for the possibility of coeliac

Congenital

disease

Destruction of the glands by radiation, surgery or

Renal function

autoimmunity

Magnesium levels

• Hypomagnesaemia (inhibits PTH secretion), which

may be due to:

Treatment

Gastrointestinal loss

• Acute symptomatic hypocalcaemia (tetany, seizures) is

Renal loss

a medical emergency and should be treated with i.v.

Drugs (diuretics, cyclosporine, alcohol)

calcium

• Drugs

20 mL of 10% calcium diluted in 100-200 saline

Calcitonin

should be infused over 10-20 min

• Increased calcium uptake by bone

Further calcium infusion may be needed (24 h slow

Hungry bone syndrome (following thyroid or para-

calcium infusion is frequently used)

thyroid surgery)

Regular monitoring of calcium levels should be

Osteoblastic bony metastasis (prostate cancer)

organized (every 4-8 h)

• Complexing of calcium from the circulation

Care should be taken against extravasation of

Acute pancreatitis (calcium soap formation due to

calcium into interstitial tissue, which may cause

fat autodigestion)

necrosis (a large vein should be used for i.v. calcium

Multiple blood transfusions (complex of calcium

administration)

with citrate)

Intravenous treatment should be followed by oral

• Functional: inability of PTH to exert its effect (PTH

calcium administration and correction of the precipi-

resistance), also known as pseudohypoparathyroidism

tating cause

Bone and calcium metabolism

• Acute hypocalcaemia with mild symptoms

Abdominal pain

Oral therapy with calcium and vitamin D is usually

Constipation

given

• Central nervous system

Correction of the underlying cause

Confusion

Patient should be carefully monitored

Depression

• Chronic hypocalcaemia

Treatment should be directed at correcting the

Investigations

underlying cause

• Plasma calcium levels: these are elevated (make sure

corrected calcium levels are used)

Hypercalcaemia

• PTH

Hypercalcaemia is commonly seen on the general medical

Raised: hyperparathyroidism

wards. Causes include:

Suppressed: non-parathyroid cause

• Increased secretion of PTH

Normal: early hyperparathyroidism (usually calcium

Primary hyperparathyroidism

levels are only mildly elevated) or familial hypocalciu-

Tertiary hyperparathyroidism

ric hypercalcaemia (FHH)

• Malignancy

• Establish the cause

Secretion of PTH-related peptide

History and full examination: this is important as it

Bony invasion in metastatic disease

may give clues to the presence of a malignant

• Familial, e.g. familial hypocalciuric hypercalcaemia

disorder

(secondary to low urinary calcium excretion)

In those with elevated PTH, the most likely diagnosis

Autosomal dominant disease due to mutation in the

is a parathyroid adenoma and localization of this can

calcium-sensing receptor

be done with: CT scan of the neck and chest, ultra-

PTH levels are usually in the normal range

sound of the neck and ^99mTc-cestamibi scan, which

It must be differentiated from primary hyperpara-

relies on concentration of the radioactive material in

thyroidism, otherwise the patient may undergo unnec-

the parathyroid tissue

essary surgery

Renal function: chronic renal failure may result in

Patient usually asymptomatic and diagnosis is made

tertiary hyperparathyroidism

by demonstrating reduced urinary calcium excretion

Chest X-ray: particularly in those with respiratory

with high plasma calcium

symptoms (exclude a malignant lung condition)

• Medications

Myeloma screen: hypercalcaemia can be one of the

Thiazide diuretics

early manifestations of multiple myeloma

Vitamin D intoxication

Vitamin D levels: to rule out vitamin D

Vitamin A intoxication

intoxication

• Granulomatous disease

24-h urinary calcium: low urinary calcium excretion

Sarcoidosis

in FHH (important to make this diagnosis as no treat-

• Endocrine causes (rare)

ment is usually required)

Hyperthyroidism

In case of suspicion, rule out endocrine causes of

Addison’s disease

hypercalcaemia: hyperthyroidism

(TFTs), adrenal

Acromegaly

failure

(synacthen test) and acromegaly

(glucose

tolerance test, if history is suggestive)

• Determine end organ damage

Clinical presentation

Ultrasound of the renal tract

Symptoms are usually insidious and include:

Skeletal radiographs

• Osmotic symptoms

Check bone mineral density

Polyuria

Polydipsia

Dehydration

Treatment

• Gastrointestinal

For severe symptomatic hypercalcaemia:

Anorexia and vomiting

• Rehydrate patient with i.v. fluid

Part 1: Basics

• Intravenous bisphosphonates

(pamidronate is fre-

Table 12 Symptoms and signs of osteomalacia and rickets.

quently used): these agents should only be given after

Osteomalacia

Rickets

adequate hydration

• Treat the cause of hypercalcaemia

Bone pain

Growth retardation

• In resistant cases calcitonin can be used

For moderate hypercalcaemia:

Fractures

Bone pain and fractures

• Ensure adequate patient hydration

Proximal myopathy

Skeletal deformities:

• Treat the underlying cause:

Bowing of tibia

Surgery for hyperparathyroidism: in mild cases, this

is not always necessary and patient can be simply fol-

Rickety rosary

lowed up with regular calcium checks and monitoring

Widening of wrists

for end organ damage

• Hypercalcaemia of malignancy may partly respond to

systemic steroids, which can be given until specific cancer

treatment is introduced

Osteomalacia and rickets

Osteomalacia and rickets are due to inadequate mineral-

ization of bone. The former occurs in mature bone,

whereas the latter occurs in growing bone. Causes of

osteomalacia and rickets include:

• Associated with low phosphate

Vitamin D deficiency (the commonest cause): low

phosphate is due to increased PTH secretion

Vitamin D-dependent rickets: due to deficient

vitamin D receptor or inadequate conversion of

vitamin D to the active form (rare)

Excessive loss of urinary phosphate (rare): onco-

genic osteomalacia (seen in malignant disease), X-

Figure 13 X-ray changes in osteomalacia. A partial fracture in

linked hypophosphataemia, renal tubular acidosis and

the femur, known as a Looser zone or pseudofracture, can be

drugs (diuretics)

seen in subjects with osteomalacia.

Decreased phosphate availability: starvation, malnu-

trition

(alcoholism in the UK is one cause) and

malabsorption

• PTH: usually elevated (except for some rare causes of

• Associated with high phosphate

osteomalacia)

Renal failure

• Vitamin D levels

The vast majority of patients will have osteomalacia/

• Bone X-ray

rickets due to vitamin D deficiency with or without renal

Pseudofractures or Looser zones: these are patho-

disease, this is what you need to remember.

gnomic of osteomalacia (see Fig. 13)

Widening of growth plates and bone deformity: seen

Clinical presentation

in rickets

Symptoms and signs of osteomalacia/rickets are sum-

Table

13 summarizes the biochemical findings in

marized in Table 12.

common causes of osteomalacia/rickets.

Investigations

Treatment

• Calcium: low or low-normal

• Vitamin D replacement

• Phosphate: usually low, except for osteomalacia due to

Calciferol can be given orally often with calcium

renal failure

supplementation

Bone and calcium metabolism

Table 13 Biochemical findings in osteomalacia/rickets caused by vitamin D deficiency and renal failure. It is important to

remember that longstanding renal failure can be associated with hypercalcaemia (rather than hypocalcaemia) due to tertiary

hyperparathyroidism.

Calcium

Phosphate

Alkaline phosphatase

25-OH-Vit D

PTH

Vit D deficiency (dietary, malabsorption)

↓

↑

↓

↑

Renal failure

↓

↑

In renal failure

1-OH vitamin D (1-α-calciferol)

Hyperthyroidism

should be given as the kidneys are unable to convert

Growth hormone deficiency

25-OH vitamin D to the active 1, 25-OH vitamin D

• Inflammatory conditions

• Treat the underlying cause

Rheumatoid arthritis

• Neoplastic disease

Osteoporosis

Multiple myeloma

• This is a very common condition, which is due to a

Clinical presentation

reduction in bone mass

The disease is usually silent until the occurrence of frac-

tures (it does not cause skeletal pain).

Box 7 Loss of bone mass and osteoporosis

• Low trauma fractures are a common presentation

• Vertebral fractures are also common resulting in:

• From the age of 40, there is a gradual loss in bone

Back pain

(usually sudden onset and well

mass (around 0.5% annually)

• Due to the protective effects of sex hormones,

localized)

osteoporosis is common in women after the menopause

Loss of height (this explains why older individuals

and is called postmenopausal osteoporosis

shrink in size!)

• In women, bone mass loss after the menopause is

Kyphosis

accelerated, which explains the higher rate of

Spinal cord compression in severe cases

osteoporotic fractures in older women compared with

men

Investigations

Measure bone mineral density (BMD) using dual energy

Causes include:

X-ray absorptiometry (known as DEXA scan):

• Gonadal failure

Establish the cause

Women: premature menopause

(physiological

Box 8 Bone mineral density (BMD)

menopause in the older age group) and any cause of

amenorrhoea

• BMD > −1: normal

Men: Kleinfelter’s syndrome and acquired

• BMD < −1 but > −2.5: osteopenia

hypogonadism

• BMD < −2.5: osteoporosis

• Drugs (long-term use)

Steroids

• Full blood count (FBC), ESR (rule out inflammatory

Heparin

condition)

Anticonvulsants

• Calcium levels

• Gastrointestinal and nutritional

• Renal function

Malabsorption due to any cause (for example coeliac

• Thyroid function

disease)

• Testosterone levels in men

Malnutrition (excessive alcohol, anorexia nervosa)

• Oestradiol and FSH/LH levels in women with early

• Endocrine disease

menopause

Hyperparathyroidism

• X-rays to rule out fractures. Back X-rays (see Fig. 14)

Cushing’s syndrome

are requested to rule out vertebral crush fractures in

Part 1: Basics

Figure 15 Typical “frontal bossing” and bowing of the bones.

Paget’s disease

The main abnormality in Paget’s disease is overactivity

of the osteoblasts resulting in bone resorption. This in

turn stimulates osteoblast function resulting in the for-

mation of new bone. Bone resorption and formation is

Figure 14 The x-ray shows a crush fracture of the vertebral

disorganized, consequently leading to bony deformities.

body (can be seen as shorter vertebral body with increased

bone density). In the presence of a crush fracture, DEXA scan

Clinical presentation

may be inaccurate in measuring vertebral bone density.

Paget’s disease mainly affects the skull, vertebrae, pelvis,

those with: significant loss of height and/or sudden-onset

femur and tibia. Therefore, the patient presents with:

back pain.

• Bone deformities (skull abnormalities, bowing of tibia)

• More tests may be required to exclude specific

(see Fig. 15)

conditions

• Bone pain

• Fractures

Treatment

• Complications

• Hormone replacement therapy (HRT)

Nerve compression (may result in deafness)

Postmenopausal women

Spinal cord compression (may result in paralysis)

Women with gonadal failure

Sarcomatous transformation (osteogenic sarcoma):

• Testosterone replacement

fortunately, a rare event

Men with gonadal failure

It should be noted that the vast majority of patients

• Calcium and vitamin D

(up to 90%) are asymptomatic and the disease is diag-

• Bisphosphonates: remain the mainstay of osteoporosis

nosed during routine laboratory investigations (raised

treatment usually in combination with calcium and

alkaline phosphatase).

vitamin D

• Strontium can be effective but makes BMD measure-

Investigations

ments unreliable (the drug is incorporated into the bone

• Alkaline phosphatase: usually elevated and can reach

structure)

very high levels

• Calcitonin can be effective in those with vertebral

• Bone X-ray:

crush fractures as it partially relieves the pain

Lytic (bone resorption) lesions

• Treatment is monitored

Sclerotic (new bone formation) lesions (Fig. 16)

Clinically: no further fractures/loss of height

• Bone isotope scan: helpful to fully assess the extent of

Repeat BMD 1-2 years after starting the treatment

bony involvement (Fig. 17)

Bone and calcium metabolism

Figure 16 Typical lytic and sclerotic lesions in Paget’s disease

of the pelvis.

Treatment

• High dose oral bisphosphonate is the mainstay of

(a)

(b)

treatment

Figure 17 An isotope bone scan showing an increased uptake

• Indications for treatment include:

in the left femur and tibia, and right elbow and (b) vertebral

Bone pain

body. Courtesy of Dr R. Bury, Radionuclide Department,

Neurological complications

University of Leeds.

Fractures

Hypercalcaemia (which is a rare complication of

Paget’s disease)

• Main abnormality is in bone architecture, resulting in:

• Monitoring therapy

Severe osteoporosis and easy fractures: these indi-

Clinical improvement

viduals usually develop multiple fractures during their

Alkaline phosphatase levels: these usually fall with

lifetime

successful treatment

Associated abnormalities include: blue sclera, abnor-

malities in teeth and hearing loss

Osteogenesis imperfecta

• A familial disease that can be inherited as autosomal

Treatment

dominant (AD) or autosomal recessive (AR)

• Bisphosphonates can partly help by:

• Several mutations are recognized leading to different

Increasing bone mass

clinical presentations

Reducing the incidence of fractures

The adrenal glands

Anatomy

• Adrenal disorders with no hormonal abnormality

• The adrenal glands are situated above the kidneys

Adrenal tumours

(Fig. 18)

• The aorta and renal arteries provide the arterial blood

Investigation for adrenal dysfunction

supply to the adrenal glands, whereas venous drainage

Hormonal tests

usually occurs into the inferior vena cava on the right and

• Static tests

left renal vein on the left

Plasma renin activity, aldosterone, androgens

• The adrenal glands are composed of:

(DHEA, testosterone), urinary catecholamines

Adrenal cortex, which represents 90% of the gland

• Suppressive tests

and produces corticosteroids (cortisol), mineralocor-

Dexamethasone suppression test

ticoid

(aldosterone) and androgens

[dehydroepi-

• Stimulating tests

androsterone (DHEA) and androstenedione]

Synacthen test

Adrenal medulla, which represents

10% of the

adrenal gland and produces catecholamines (adrena-

Imaging tests

line, noradrenaline and dopamine)

• CT or MRI: can detect lesions >5 mm in diameter

• The adrenal gland is under the control of:

• Ultrasound: can detect lesions >20 mm in diameter

Pituitary adrenocorticotrophic hormone

(ACTH)

but can be technically difficult

(steroid and androgen production)

• Venous sampling: can be used to investigate hormonal

Renal renin (aldosterone production)

production by the glands, particularly in the presence

of pathology in both adrenals (helps to differentiate

Pathophysiology of the adrenal glands

unilateral from bilateral disease)

Disorders of the adrenal glands include:

Full details of the above tests will be given under each

• Excess production of adrenal hormones, which result

disease entity (described below).

in different clinical entities:

Glucocorticoids: Cushing’s syndrome

Overproduction of adrenal hormones

Mineralocorticoids: hyperaldosteronism

Glucocorticoid excess

Androgens: adrenal tumours, congenital adrenal

Excessive secretion of glucocorticoid by an adrenal

hyperplasia

adenoma results in Cushing’s syndrome with similar

Catecholamines: pheochromocytoma

symptoms to ACTH-dependent Cushing’s syndrome,

• Hormonal undersecretion (adrenal failure)

except for the absence of pigmentation (because ACTH

Glucocorticoid and mineralocorticoid: Addison’s

levels are suppressed). Causes of Cushing’s syndrome are

disease

summarized in Table 14.

Lack of androgen and catecholamine production

not believed to have significant clinical

Clinical presentation

manifestations

Onset is often insidious and symptoms may fluctuate.

Patient presents with:

• Weight gain

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

• Central obesity with thin extremities

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

• Acne and hirsutism

The adrenal glands

Cortex

Medulla

Red cheeks

Moon face

Fat pads

Cut-section of adrenal gland

Left adrenal

Right adrenal

gland

Bruisabillity

gland

with ecchymoses

Striae

Pendulous

Thin skin

abdomen

Proximal

myopathy

Right kidney

Left kidney

Figure 18 Anatomy of the adrenal glands.

Poor wound

healing

Table 14 Causes of ACTH-dependent and ACTH-independent

Cushing’s syndrome.

Figure 19 Clinical features of Cushing’s syndrome (see text for

ACTH-dependent

ACTH-independent Cushing’s

full explanation).

Cushing’s syndrome

syndrome

Investigations

Pituitary tumour secreting

Adrenal tumour secreting

• Confirm the presence of excess cortisol

ACTH (Cushing’s disease)

glucocortocoid (ACTH levels are

Midnight cortisol: in normal individuals, cortisol

suppressed)

levels at midnight during sleep are undetectable. This

Ectopic ACTH production

Long-term steroid treatment

test may be difficult to arrange as the patient needs to

(malignant tumours)

(respiratory disease, connective

be admitted and a blood sample should be taken

tissue disease)

immediately after the patient is woken up at midnight

(the patient should not be warned about having this

test)

24-h urinary cortisol: high levels are suggestive of the

• Easy bruising

diagnosis

• Low libido and menstrual irregularities

Overnight dexamethasone suppression test: give

• Growth arrest in children

0.5-1.0 mg of dexamethasone at 23:00 and measure

Signs include (see Fig. 19)

cortisol at 09:00. Cortisol levels less than 50 nmol/L

• Facial appearance (moon-like face), with hirsutism

effectively rule out the diagnosis of Cushing’s

and thinning of scalp hair

syndrome

• Central obesity and abdominal striae

Low-dose dexamethasone suppression test: give

• Thin skin and evidence of bruising

0.5 mg dexamethasone ever 6 h for 2 days (eight doses)

• Proximal muscle weakness

and check cortisol levels thereafter, which should be

• Hypertension

<50 nmol/L in the absence of Cushing’s syndrome

• Fractures (secondary to osteoporosis)

• Differentiate between different causes of Cushing’s

• Diabetes mellitus or impaired glucose tolerance

syndrome

• Increased pigmentation does not occur in adrenal

ACTH levels: these are suppressed in adrenal

disease as ACTH levels are not increased (ACTH produc-

Cushing’s but detectable in pituitary Cushing’s disease

tion is suppressed due to negative feedback)

or cases due to ectopic ACTH production

Part 1: Basics

Table 15 Causes of increased aldosterone production.

Angiotensinogen

Renin

Renin-dependent

Renin-independent

(produced in

hyperaldosteronism (raised

hyperaldosteronism

the kidneys)

plasma renin activity)

(suppressed plasma renin

Angiotensin I

activity)

Renal hypoperfusion (renal

Aldosterone-producing adrenal

artery stenosis, severe heart

adenoma (Conn’s syndrome)

Angiotensin II

failure, cirrhosis)

and rarely carcinoma

Renin-producing tumour (rare) Bilateral adrenal hyperplasia

High-dose dexamethasone suppression test: give

≠ BP

2 mg dexamethasone every 6 h for 2 days. If cortisol is

suppressed to more than 50% of basal value, it suggests

a diagnosis of pituitary Cushing’s disease, ruling out

the possibility of adrenal Cushing’s syndrome

• Imaging

≠ Na⁺ absorption

CT or MRI of the adrenal: shows a mass in adrenal

≠ K⁺ excretion

Aldosterone

(by renal tubules)

Cushing’s syndrome

Signs of malignant adrenal mass include: large size

(>6 cm), heterogeneity (calcification and necrosis) and

local invasion

Figure 20 Control of aldosterone secretion. Decreased

perfusion pressure in the kidneys results in renin secretion and

Treatment

the conversion of angiotensinogen to angiotensin I, and

• Surgery for benign adrenal adenoma: prognosis is

subsequently to angiotensin II (ATII) by angiotensin converting

good

enzymes. ATII stimulates the adrenal glands to produce

• Surgery followed by adrenolytic treatment (i.e. mito-

aldosterone, which increases sodium reabsorption and

tane) for adrenal carcinoma: prognosis is poor as only

potassium excretion by the renal tubules. Increased plasma

one in five individuals survive for 5 years

sodium results in water retention consequently raising the

blood pressure and switching off renin secretion (negative

Mineralocorticoid excess

feedback). Furthermore, low potassium has a negative

This results from the increased production of aldoste-

feedback effect on aldosterone secretion. AG, adrenal gland;

BP, blood pressure.

rone. Causes of increased aldosterone production are

summarized in Table 15 (see also Fig. 20).

• Signs are moderately severe hypertension, particularly

Box 9 Primary hyperaldosteronism

in a younger individual

Primary hyperaldosteronism results in:

Investigations

• Renal sodium retention

Hypertension with hypokalaemic alkalosis should be

• Potassium and hydrogen ion loss

investigated for the possibility of hyperaldosteronism.

• Consequently leading to hypertension, hypokalaemia

• Raised aldosterone/renin ratio is highly suggestive of

and metabolic alkalosis

the diagnosis

• Imaging

Clinical presentation

CT or MRI of the adrenals: differentiates between

• Often asymptomatic and diagnosis is made during

adrenal adenoma and bilateral hyperplasia

investigation for hypertension

Adrenal vein sampling: reserved for difficult cases

• Patients sometimes experience symptoms related to

hypokalaemia such as muscle weakness and myopathy,

Treatment

and polyuria

• For adrenal adenoma (Conn’s syndrome), surgery is

The adrenal glands

the treatment of choice, which cures hypertension in

• Surgery

two-thirds of cases

• Drugs

• For bilateral adrenal hyperplasia, the aldosterone

β-blocker (without previous α-blockade)

antagonist, spironolactone or potassium-sparing diure-

Anaesthetics

tics, amiloride or triamterene, are used

Opiates

Antidepressants

Catecholamine excess

Pheochromocytomas can be part of a syndrome as

Adrenal medullary tumours (pheochromocytomas) can

shown in Table 17.

produce adrenaline and noradrenaline resulting in

hypertension.

Investigations

• 24 h urine collection for catecholamines: due to the

Clinical presentation

episodic nature of the disease, plasma levels of catechol-

A pheochromocytoma should be suspected in:

amines can be normal and, therefore, measurement of

• Severe or resistant hypertension

these hormones in the urine is more reliable (two to three

• Hypertension in the young

collections are necessary)

• Hypertension associated with the symptoms and signs

• Plasma catecholamines: this can be useful if samples

summarized in Table 16

are collected during a crisis

Symptoms are episodic and similar to how you feel

• Suppression tests (pentolinium or clonidine suppres-

when you are angry or before sitting an important

sion): rarely needed to make a diagnosis

exam.

• Imaging

Patients may present with a hypertensive crisis, which

CT or MRI of adrenals: usually reveal a large adrenal

can be fatal. Factors precipitating a crisis include:

tumour

• Exercise

Body MRI: if suspected extra-adrenal tumours

• Pressure on the abdomen

(such as abdominal

Meta-iodobenzylguanidine (MIBG) scan: can detect

examination)

two-thirds of pheochromocytomas. Useful for investi-

gating extra-adrenal tumours

Table 16 Symptoms, signs and complications of

• Adrenal venous sampling

pheochromocytomas.

Reserved for difficult cases

Presence of bilateral pathology

Symptoms

Signs

Complications

Sweating

Hypertension

Cardiomyopathy

Treatment

• Surgery: removal of the tumour is curative

Pallor or flushing

Postural hypotension Heart failure

• Patient should be prepared before surgery with ade-

Feeling of

Diabetes (rare)

quate α-blockade to avoid a hypertensive crisis, which

apprehension

may be fatal

Palpitations

Stroke

• Medical treatment is not an option

The ‘rule of 10’ should be remembered when consider-

Throbbing headaches

ing pheochromocytomas:

Table 17 Syndrome associated with

MEN II

Von-Hippel Lindau

Neurofibromatosis

pheochromocytomas (MEN, multiple

endocrine neoplasia).

Hyperparathyroidism

Cerebellar and retinal

Multiple neurofibromas

haemangioblastomas

Thyroid carcinoma

Renal cell carcinoma

Café au lait spots

Pheochromocytoma (50%)

Pheochromocytoma

Pheochromocytoma (rare)

(around 20%)

Part 1: Basics

• 10% are malignant

Clinical presentation

• 10% are extra-adrenal (arising in the sympathetic or

• In glucocorticoid deficiency, presentation is similar to

parasympathetic chain)

that described under pituitary failure except for the pres-

• 10% are familial (in which case screening should be

ence of pigmentation (secondary to high ACTH) and this

preformed)

can be seen in:

Palmar creases

Adrenal failure

Scar tissue

• Primary adrenal failure results in glucocorticoid and

Buccal mucosa

mineralocorticoid deficiency

(commonly described as

• Aldosterone deficiency, resulting in:

Addison’s disease)

Postural hypotension

• Secondary adrenal failure results in glucocorticoid

Hyponatraemia

deficiency only

Hyperkalaemia

Causes of adrenal failure are summarized in Table 18.

Metabolic acidosis

Isolated aldosterone deficiency may be secondary to

Table 18 Causes of adrenal failure.

impaired renin secretion (hyporeninaemic hypoaldoste-

ronism). This is also known as renal tubular acidosis type

Primary adrenal

Secondary adrenal

IV, which can be seen in renal disease (such as diabetic

insufficiency

nephropathy), and it is a condition that is probably

underdiagnosed.

Autoimmune (main cause in

Autoimmune disease:

the Western world)

autoimmune hypophysitis,

Investigations

isolated ACTH deficiency

• Disease should be suspected in the presence of:

Infiltrative disease:

Infiltrative disease: sarcoidosis,

Hypotension

haemochromatosis,

histiocytosis,

Hyponatraemia

amyloidosis

haemochromatosis

Hypokalaemic acidosis

Infections: tuberculosis, fungal

Infections: tuberculosis,

• Random serum cortisol

infections, opportunistic

pituitary abscess

Undetectable cortisol is diagnostic of adrenal

infections (seen in patients

insufficiency

with AIDS)

• ACTH stimulation test (commonly known as synac-

Vascular

then test)

Failure of cortisol to rise after ACTH stimulation is

Haemorrhage (anticoagulant

Haemorrhage

therapy, meningococcal

diagnostic of adrenal insufficiency

septicaemia)

• Renin and aldosterone

Aldosterone levels are low and renin levels are

Infarction

elevated in primary adrenal insufficiency

Adrenoleucodystrophy: an

Radiotherapy

• Establish the cause

inherited disease, associated

Adrenal autoantibodies

with quadriplegia

Adrenal imaging

Congenital adrenal

Head trauma

hyperplasia

Treatment

Emergency treatment is required in anyone with sus-

Drug induced

pected adrenal insufficiency.

Ketoconazole (↓ cortisol

Long-term steroid treatment

• Acute treatment

synthesis)

results in suppression of

Intravenous hydrocortisone

ACTH production

Rifampicin (↑ cortisol

Intravenous fluid

metabolism)

Watch for hypoglycaemia and correct as necessary

• Chronic treatment

Malignant disease with

adrenal metastasis

Oral hydrocortisone given in two to three daily doses

(to replace glucocorticoids)

The adrenal glands

Oral fludrocortisone

(to replace mineralo-

characterized by a deficiency of one of the enzymes

corticoids)

involved in cortisol biosynthesis (fully discussed in the

Treatment is monitored clinically and by measure-

reproductive section). The commonest is due to 21α-

ment of electrolytes and plasma renin levels

hydroxylase deficiency, which results in:

• Patient education: all patients should be warned to

• Failure of cortisol and aldosterone synthesis

double the dose of glucocorticoid in mild intercurrent

• Increased production of

17-OH-progesterone and

illness and to give parenteral treatment in severe illness

testosterone

or prior to major surgery

The clinical spectrum is very wide and includes:

• In severe cases (severe deficiency)

Adrenal tumours

Salt wasting in the neonatal period

(male or

Adrenal tumours can be picked up during routine inves-

female).

tigations for non-adrenal disease and these are often

Virilization of female fetus (affected female subjects

called ‘incidentalomas’.

are sometimes raised as males)

• Less severe cases (mild deficiency), these are usually

Box 10 Investigation of adrenal tumours

clinically evident in females:

Hirsutism

Any adrenal tumour should be investigated for the

Acne

possibility of:

Menstrual irregularities

• Glucocorticoid production (i.e. Cushing’s syndrome)

Infertility

Cortisol suppression tests

• Mineralocorticoid production (i.e. Conn’s syndrome)

Investigations

High aldosterone/renin ratio

High levels of hormones upstream of the enzymatic

• Catecholamine production (i.e. pheochromocytoma)

defect (elevated 17-OH-progesterone levels).

High catecholamines on 24-h urine collection

• Androgen production (i.e. androgen-secreting tumours)

• High plasma androgen levels

Treatment

• Cortisol replacement to suppress ACTH production,

Adrenal tumours may be non-functional

(do not

thereby limiting androgen production. Response to

produce any hormones) and these can be simply followed

therapy is monitored:

up by repeated scanning. Adrenalectomy is advised for:

Clinically

• Large tumours (>4 cm)

By assessing

17-OH-progesterone levels

(aim to

• Tumours with fast growth

suppress to around twofold of normal)

(Large and fast growing tumours are more likely to be

• Fludrocortisone in severe cases with salt wasting.

malignant.)

Response to therapy is monitored:

Clinically

Congenital adrenal hyperplasia (CAH)

Renin levels

(aim to suppress into the normal

Congenital adrenal hyperplasia is an inherited disease

range)

The reproductive system

Anatomy

• The hypothalamus produces gonadotrophin releasing

The reproductive endocrine organs include the ovaries in

hormones (GnRH) in a pulsatile fashion

females and testes in males.

• GnRH stimulate the pituitary to release follicle stimu-

• The ovaries are situated in the pelvis on either side of

lating hormone (FSH) and luteinizing hormone (LH)

the uterus as shown in Fig. 21.

• FSH results in:

• During reproductive life, the ovaries contain follicles

Growth and maturation of ovarian follicles (which

(each containing an oocyte) at different stage of matura-

contain the oocyte)

tion embedded in the ovarian stroma

Stimulation of oestrogen production by follicular

• In adults, the testes are found in the scrotum, except in

cells

a minority with testicular mal descent, in which case the

• LH results in:

testicles can be in the inguinal canal

Ovulation (a surge in LH production is responsible

• In an adult male the testicular size is 15-25 ml (Fig.

for ovulation)

22)

Maintenance of progesterone production by the

• Testes are composed of:

corpus luteum

Interstitial or Leydig cells, which produce

• Inhibin, secreted by the ovaries and under FSH control,

testosterone

has a negative feedback effect on FSH production

Seminiferous tubules made up of germ (producing

• Oestradiol has a negative feedback effect on FSH pro-

sperm) and sertoli cells (producing inhibin)

duction but has a positive effect on LH surge (necessary

Full description of the female and male reproductive

for ovulation)

systems can be found in many other textbooks.

Physiology

• Ovaries have two functions

Box 11 The menstrual cycle

Endocrine: production of oestrogen and

The menstrual cycle can be divided into:

progesterone

• Follicular phase (day 6-13): around 20 follicles (each

Reproductive: storage and release of oocytes

containing an oocyte) grow under the influence of FSH

• Testicles have two functions

and secrete oestradiol

Endocrine: production of testosterone

• Ovulation (day 14): a surge in LH results in ovulation

Reproductive: production of sperms

(one oocyte is passed into the fallopian tubes)

This section will mainly concentrate on the endocrine

• Luteal phase (day 15-25): after ovulation the corpus

function of these organs.

luteum forms from theca interna cells, which produce

progesterone

Physiology of the female reproductive system

• Premenstrual phase (day 25-28): LH levels fall, and

• Ovarian function is under the control of the

theca cells lose the ability to maintain adequate

progesterone production

hypothalamic-pituitary axis (Fig. 23)

• Menstruation (day 1-6): low progesterone levels lead to

loss of endometrial support, which starts shedding and

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

menstruation takes place

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

Part 1: Basics

Hypothlamus

-/+

GnRH

(pulsatile)

GnRH

(pulsatile)

Pituitary

-/+

FSH and LH

Testis

FSH and LH

Ovaries

Inhibin

Testosterone

(Sertoli cells)

(Leydig cells)

Figure 24 The hypothalamic-pituitary-testicular axis.

Gonadotrophin (GnRH) secreted in pulsatile fashion, stimulates

Inhibin

Oestradiol

FSH and LH production by the pituitary. FSH is responsible for

sperm maturation and also controls inhibin production. LH

stimulates testosterone secretion by Leydig cells. Inhibin has a

Progesteron

negative feedback effect on FSH production, whereas

testosterone mainly suppresses LH production.

Figure 23 The hypothalamic-pituitary-ovarian axis.

Gonadotrophin (GnRH), secreted in pulsatile fashion, stimulate

follicle stimulating hormone (FSH) and luteinizing hormone

• Hypothalamic GnRH, secreted in pulses, regulate FSH

(LH) production by the pituitary. FSH results in follicular growth

and LH secretion by the pituitary

and maturation in the ovary associated with oestradiol

• FSH is important for sperm maturation

production. LH results in ovulation and subsequently maintains

• LH is important for testosterone production by Leydig

progesterone production by corpus luteum theca cells. Inhibin

cells

secretion by the ovaries, stimulated by FSH, has a negative

• Inhibin, produced by sertoli testicular cells and under

feedback effect on pituitary FSH production. Oestradiol has a

FSH control, has a negative feedback effect on FSH

negative feedback effect on FSH production but it facilitates

production

the LH surge necessary for ovulation.

• Testosterone has a negative feedback effect, which

• Effects of hormonal changes on the uterine endome-

mainly affects LH production

trium include:

Repair and proliferation of the endometrium

Pathophysiology of the endocrine

(oestradiol)

reproductive system

Increase endometrial thickness and preparation for

Abnormalities of the female reproductive system:

implantation (progesterone)

• Menstrual abnormalities

• Premature ovarian failure

Physiology of the male reproductive system

• Polycystic ovary syndrome (PCOS)

• Similarly to the ovaries, testicular function is under the

• Congenital adrenal hyperplasia

control of the hypothalamic-pituitary axis (Fig. 24)

• Virilizing tumours

The reproductive system

• Infertility

• Rule out physiological causes

Abnormalities of the male reproductive system:

• Establish growth and development of the child

• Hypogonadism

(particularly in primary amenorrhoea)

• Gynaecomastia

• Details of previous menstrual cycle (if any)

• Testicular tumours

• Any recent stress/weight loss

• Infertility

• Past or present illness

• History of radiation or chemotherapy

Menstrual abnormalities

• Previous pelvic operation or pelvic inflammatory

This topic is covered in detail in other textbooks and is

disease

only briefly discussed here. Menstrual abnormalities can

• Review drug history as some medications can cause

be divided into:

amenorrhoea, e.g. previous use of oral contraceptive

pills

Physiological

• Presence of galactorrhoea

• Prepubertal

• Pregnancy

Investigations

• Lactation

Only hormonal investigations will be listed here. These

• Menopause

include plasma levels of oestradiol, FSH, LH and prolac-

tin and sex hormone binding globulin (SHBG).

Pathological

• Low ovarian hormones and raised FSH/LH indicates

Primary amenorrhoea: the failure to reach menarche by

primary ovarian failure

(menopause or premature

the age of 16. This may be due to:

ovarian failure)

• Structural abnormality (such as imperforated hymen,

• Low ovarian hormones with low FSH/LH indicates

congenital absence of the uterus)

pituitary or hypothalamic disease

• Genetic disorders (such as Turner’s syndrome)

• Prolactin should always be checked as raised levels

• Testicular feminization syndrome: the individual is

result in suppression of GnRH production and sub-

genetically a male (XY chromosome) but phenotypically

sequent menstrual irregularities (see pituitary section)

a female due to tissue insensitivity to androgens

• Thyroid and/or adrenal abnormalities should be

• Causes of secondary amenorrhoea (see below)

excluded in suspicious cases

Secondary amenorrhoea: the cessation of menstrual

• Karyotype in suspected conditions: Turner’s syndrome

periods in women who had previously menstruated.

(XO), testicular feminizing syndrome (XY)

Causes include:

• Ovarian, e.g. polycystic ovary disease, or premature

Treatment

ovarian failure due to a chromosomal abnormality

• Treat the cause

(Turner’s syndrome), autoimmune disease or iatrogenic

• Hormone replacement therapy should be considered

cause

(chemo- or radiotherapy, e.g. after cancer

in those with irreversible disease

treatment)

• Uterine or fallopian tubes, e.g. adhesion in the uterus/

Premature ovarian failure

fallopian tubes or uterine tumours

This is defined as the development of menopause (low

• Pituitary, e.g. hypopituitarism or prolactinoma

oestrogen and raised gonadotrophins) before the age of

• Hypothalamic, e.g. excessive exercise (such as profes-

40. Causes include:

sional athletes), severe weight loss, stress (physical or

• Chromosomal abnormalities: Turner’s syndrome

psychological), hypothalamic tumours or infiltrative

The commonest X chromosome abnormality in

lesions

females affecting 1 in 2500

• General endocrine, these are usually associated with

There is a complete or partial absence of one X

menstrual irregularities rather than amenorrhoea and

chromosome

include thyroid dysfunction and Cushing’s syndrome

Characteristic phenotype

(Fig.

25, colour plate

Clinical presentation

section) comprises short stature, webbed neck, widely

The patient presents with amenorrhoea or menstrual

spaced nipples and poor breast development, cubitus

irregularities. It is important to establish in the history:

valgus and shortened metacarpals

Part 1: Basics

Associated clinical abnormalities include aortic

Clinical presentation

coarctation, left-sided heart defects, hypothyroidism

• Hirsutism

and lymphoedema

Face, abdomen, back and extremities

• Autoimmune disease of the ovary

95% of women presenting to the outpatient clinic

Can be associated with other organ-specific autoim-

with hirsutism have PCOS

mune disease (thyroid, type 1 diabetes, etc.)

Symptoms often begin around puberty

• Iatrogenic

• Oligo- or amenorrhoea: secondary to unovulation

Chemotherapy

• Obesity: the majority of these patients are overweight

Radiotherapy

• Complications

• Infections

Infertility

Human immunodeficiency virus (HIV)

Endometrial carcinoma: absence of menstruation

Mumps

and regular shedding of the endometrium predisposes

to endometrial carcinoma

Clinical presentation

Investigations

• Subjects present before the age of 40 with oligo- or

• Plasma levels of the following hormones should be

amenorrhoea

checked:

• Symptoms of oestrogen deficiency

Testosterone: usually raised

Hot flushes

Sex hormone binding globulin: usually low

Mood swings

LH/FSH ratio: raised in two-thirds of patients

Fatigue

• Imaging

Dyspareunia

Ultrasound of the ovaries shows multiple cysts in the

stroma in the majority of subjects (Fig. 26)

Investigations

Measurement of endometrial thickness is also useful,

• The combination of low oestradiol and high FSH/LH

which demonstrates endometrial hyperplasia

confirms the diagnosis

• Other tests: due to the association with insulin resis-

• Tests should be undertaken to investigate the cause as

tance patients should be screened for:

appropriate

Diabetes

Karyotype

Lipid abnormalities

Pelvic imaging

Complications

• Osteoporosis

• Increased risk of cardiovascular disease

Treatment

• Hormone replacement therapy

Polycystic ovary syndrome (PCOS)

• A very common condition

• The leading cause of hirsutism in women

• Characterized by:

Insulin resistance

Hyperandrogenaemia and low sex hormone binding

globulin (SHBG) (hence, high levels of free testosterone)

Polycystic ovaries in the majority of cases

Figure 26 Ultrasound of the ovaries showing multiple cysts, a

Failure of ovulation

characteristic finding in polycystic ovary syndrome. Courtesy of

Most patients are overweight

Professor S. Atkin.

The reproductive system

Treatment

• Anti-androgen agents

These are a number of different treatments, which are

Androgen receptor blockers such as spironolactone,

summarized in Table 19.

cyproterone acetate and flutamide (the latter rarely

• Weight loss: this reduces insulin resistance and, conse-

used due to risk of hepatic toxicity)

quently, hyperandrogenaemia

5α-reductase inhibitors such as finasteride, which

• Suppression of ovarian androgen production

blocks the conversion of testosterone to its more potent

Oral contraceptive pills suppress FSH/LH pro-

androgen, dehydrotestosterone

duction, and increase SHBG and thus reduce free

• Insulin sensitizers

testosterone levels

Metformin: can be helpful in some patients and may

induce ovulation

Thiazolidinediones (glitazones): generally inferior to

Table 19 Summary of treatment options for polycystic ovary

metformin

syndrome.

• Local cosmetic treatment for hirsutism

Agent

Mode of action

Epilators

Creams

Oral contraceptive pills

Suppression of ovarian stimulation

Electrolysis

Laser therapy

Increase in sex hormone binding

• Fertility treatment (to induce ovulation)

globulin

Clomiphene citrate

Spironolactone

Anti-androgen

GnRH preparations

Cyproterone acetate

Laparoscopic ovarian surgery

Flutamide

Congenital adrenal hyperplasia

Finasteride

• An autosomal recessive condition, which results in a

defect in one of the enzymes involved in the synthesis of

Metformin

Insulin sensitizers

steroid hormones (Fig. 27)

Thiazolidinedione

• The commonest is 21α-hydroxylase (90%) and less

Clomiphene

Induction of ovulation

commonly 11β-hydoxylase (<10%). Other enzyme defi-

ciencies are rare

Gonadotrophins

(Fertility treatment)

Surgery

21α-hydroxylase deficiency (see Fig. 27 )

This leads to:

Epilators, electrolysis, laser

Cosmetic measures

• Cortisol deficiency, which may cause an Addisonian

therapy

crisis in severe cases

Cholesterol

Pregnenolone

17OH- Pregnenolone

DHEA

Progesterone

17OH- Progesterone

Androstenedione

21-hydroxylase

DOC

11-Deoxycortisol

Testosterone

11-hydroxylase

Corticosterone

Cortisol

Figure 27 Synthesis of adrenal

hormones. DHEA,

dehydroepiandrosterone; DOC,

Aldosterone

deoxycorticosterone.

Part 1: Basics

• Aldosterone deficiency, resulting in salt loss and

• Elevated ACTH plasma levels (due to defective cortisol

hypotension

production)

• Loss of negative feedback on the pituitary results in

• Hormonal abnormalities can be minimal in non-

increased ACTH secretion and excessive production of

classical CAH and, therefore, ACTH stimulation test

17-OH-progesterone, subsequently resulting in increased

may be required to make the diagnosis (raised 17-OH-

testosterone production and virilization

progesterone after synacthen test)

• Severity of the disease varies and depends on whether

the individual has complete or partial enzyme

Treatment

deficiency

• Steroid treatment: this results in ACTH suppression

and subsequently reduction in adrenal androgen

11β-hydroxylase deficiency (see Fig. 27 )

production

This leads to:

• Fludrocortisone may be required in those with high

• Increased androgen production resulting in

renin levels

virilization

• Bilateral adrenalectomy in subjects with severe

• Increased corticosterone (DOC) accumulation result-

virilization

ing in hypertension

Virilizing tumours

Clinical presentation

These include tumours of the ovaries or adrenal glands,

Only the common 21α-hydroxylase deficiency will be

which can be benign or malignant.

discussed here, which can present in two forms:

Clinical presentation

Complete 21α-hydroxylase deficiency (classical CAH)

Adrenal or ovarian virilizing tumours should be sus-

• Female

pected in:

Virilization

• Rapid onset of symptoms and

signs of

Clitoromegaly

hyperandrogenism

Labial fusion

• Virilization

(severe hyperandrogenism),

manifested

Renal salt wasting, resulting in hypotension

as:

• Males

Clitoromegaly

Renal salt wasting

Increased muscle mass

Reduced fertility due to suppression of gonadotro-

Deepening of voice

phin secretion secondary to high adrenal testosterone

Frontal balding

production

• Symptoms related to the tumour

Abdominal mass

Partial 21α-hydroxylase deficiency

Ascites

(non-classical CAH)

• Female

Investigations

Hirsutism

• Testosterone levels are usually very high

Acne

Imaging of adrenal/pelvis

Menstrual abnormalities

Ultrasound

Infertility

CT or MRI scan

• Male

Usually asymptomatic

Treatment

Investigations

• Surgery

• Raised testosterone plasma levels

• Prognosis

• Raised 17-OH-progesterone plasma levels

In benign disease: excellent

• Elevated renin plasma levels (due to defective produc-

In malignant disease: generally poor with 20-40%

tion of aldosterone)

5-year survival

The reproductive system

Male hypogonadism

Tiredness

Defined as the failure of the testes to produce spermato-

Decreased facial and/or body hair

zoa and/or testosterone. Causes of male hypogonadism

Reduced libido

include:

• The following can be found on examination:

Increased height: low testosterone in childhood

Primary

results in delayed closure of epiphysis

• Kleinefelter’s

syndrome

(hypergonadotrophic

Decreased facial and/or body hair

hypogonadism)

Small penis (usually in prepubertal disease)

Occurs in 1 : 500 births

Small testes

Sex chromosome abnormality (47 chromosomes

Anosmia

XXY)

Gynaecomastia (discussed below)

Individuals are usually tall

Evidence of chronic disease (liver, renal, etc.)

Gynecomastia is common with increased risk of

• It should be noted that clinical presentation depends

breast cancer

on:

Intellectual dysfunction is found in around half the

Severity (partial or complete)

individuals

Age of onset

• Crytorchidism: failure of testes to migrate into the

Duration of sex hormone deficiency

scrotum (undescended testes)

• Orchitis (testicular inflammation)

Investigations

• Previous chemotherapy or radiotherapy

• Testosterone, FSH, LH and prolactin should be

• Testicular trauma

checked

• Alcohol excess

• Low testosterone with elevated FSH and LH indicates

• Chronic illness

primary hypogonadism

• Low testosterone with low/normal FSH and LH indi-

Secondary

cates secondary hypogonadism

• Hypothalamic

• Normal levels of testosterone/FSH/LH and prolactin

Hypothalamic tumours or infiltrative disease

usually rule out hypogonadism secondary to endocrine

Kallman’s syndrome: a genetic disease characterized

abnormality

by hypogonadotrophic hypogonadism and anosmia

• Sex hormone binding globulins are usually requested

(impaired sense of smell) in the majority

to enable calculation of free testosterone index, which

Idiopathic hypogonadotrophic hypogonadism:

gives a more accurate measurement of functional or

similar in presentation to Kallman’s syndrome but

active testosterone hormone levels

sense of smell is intact

Severe exercise

Treatment

Severe weight loss

• Treat the cause

Stress (physical or emotional)

• In cases of irreversible disease:

Systemic illness

Testosterone replacement: transdermally, testoster-

• Pituitary

one (as a gel) can be applied to the skin once a day;

Tumours

or by injections, these can be given every few

Infarct

weeks and with the newer preparations every few

Infiltrative disease

months

In cases of secondary irreversible gonadal failure,

Clinical presentation

treatment with GnRH is a possibility in order to restore

• Failure of progression through puberty

fertility

• Infertility

Sexual dysfunction (unable to maintain or absence

of erection)

Gynaecomastia

• Symptoms related to testosterone deficiency

Enlargement of the male breast is a relatively common

Hot flushes

condition. Causes include:

Part 1: Basics

• Physiological

Treatment

Puberty

• Treat the underlying cause

Familial

• Surgical treatment in severe cases

(reduction

• Drugs

mammoplasty)

Digoxin

Oestrogens

Infertility

Spironolactone

Failure of pregnancy after 1 year of regular unprotected

Opiates

sex is defined as infertility. This can be very complicated

Antipsychotics

to investigate.

Heroin

Alcohol

• Hypogonadism (any cause, see above)

• Oestrogen or androgen producing tumours

Box 12 Causes of infertility

• Chronic illness

Causes of female infertility

Liver cirrhosis

• Hypothalamic abnormality

Renal failure

Hypothalamic amenorrhoea is commonly found in

• Breast cancer

young athletes who undergo rigorous exercise

Kallman’s syndrome

Clinical presentation

• Pituitary abnormality affecting gonadotrophin secretion

Pituitary tumours

• Patient presents with breast enlargement. Particular

Infiltrative disease

care should be taken in:

• Primary gonadal failure/abnormality

Rapid growth

PCOS

Associated pain or tenderness

Turner’s syndrome

• Hypogonadal symptoms (see above)

Primary ovarian failure

• Drug history is essential

(including recreational

Chemotherapy or radiotherapy

drugs)

• Tubular lesions

• Examination

Adhesions due to previous infections

Palpate the breast: universal enlargement, lump,

Endometriosis

look for galactorrhoea

• Uterine abnormalities

Palpate the testicles: rule out tumour and measure

Congenital abnormalities

Adhesions due to previous infection

testicular size

Fibroids

Look for evidence of systemic illness

• Systemic debilitating disease

Causes of male infertility include:

Investigations

• Hypothalamic disease

• Blood tests

• Pituitary disease

Testosterone

• Testicular abnormality

Oestradiol

FSH/LH

Prolactin

Human chorionic gonadotrophin (hCG, raised in

Investigations

some malignant tumours)

This is done in specialized centres. Briefly:

Liver, renal and thyroid function

• Imaging

Male partner

Breast mammography if tumour is suspected

Semen analysis

Testicular ultrasound

• Normal: investigate female partner

CT abdomen if adrenal lesion is suspected

• Abnormal

• Biopsy

Endocrine tests: normal testosterone, FSH, LH and

Breast tissue biopsy if tumour is suspected

prolactin usually rules out an endocrine cause; low

The reproductive system

testosterone with high LH indicates primary gonadal

Precocious puberty

failure; low testosterone with low/normal LH suggests

• Onset of puberty before the age of 8 in girls and 9 in

secondary hypogonadism

boys. Causes include:

karyotyping in suspected Kleinfelter’s syndrome

Familial or idiopathic

Testicular ultrasound may show features of inflam-

Intracranial tumours

mation or testicular tumour

Rare genetic defects resulting in sex hormone pro-

duction independent of central control

Female partner

• Endocrine tests

Delayed puberty

Normal testosterone, oestradiol, FSH, LH, TFTs and

• Failure to progress to puberty after the age of 14 in girls

prolactin makes an endocrine cause for the infertility

and 16 in boys. Causes include:

unlikely

Constitutional delay: fortunately the commonest

Abnormalities with the above hormones should be

cause

investigated as discussed earlier

Chronic disease during the childhood period

• Investigate for structural tubular and uterine

Hypergonadotrophic hypogonadism: Kleinfelter’s

abnormalities

syndrome and Turner’s syndrome

Hypogonadotrophic hypogonadism: Kallman’s

Treatment

syndrome and disorders of the hypothalamus and

• Treat the cause

pituitary

• Ovulation induction

• In some cases no cause for infertility is found and

Investigations

intrauterine insemination

(IUI) or IVF may be

• Blood tests

considered

Testosterone

Oestradiol

Puberty

FSH/LH

• Average age of onset in girls is 10-12 years and boys

Prolactin

12-13 years

Karyotype

• Puberty involves breast development (the first sign),

• Imaging of:

appearance of pubic hair and menarche in girls, whereas

Ovaries

in boys it includes testicular and penile enlargement,

Testes

appearance of pubic hair, voice change and increase in

Pituitary/hypothalamus

facial hair

• Puberty has five different stages (Tanner’s stages) in

girls and boys with specific measures applied to the

Treatment

parameters outlined above

• Treat the cause

The pancreas

Anatomy

• Around 2-3 million individuals in the UK have diabe-

• The pancreas is situated behind the posterior wall of

tes but only half of them are diagnosed with the disease;

the abdomen (Fig. 28)

in the rest the condition is clinically silent

• It can be divided into:

Head: located within the duodenal curve

Classification of diabetes

Body connected to the head through a slight con-

Type 1 diabetes (5-15% of cases)

striction (neck)

• This is an autoimmune condition, resulting in destruc-

Tail representing tapering of the body as it extends

tion of pancreatic β-cells

to the left approaching the gastric surface of the

• Subjects are often young (children or young adults)

spleen

but the older age group can also be affected

• The anterior surface of the pancreas is covered by the

• Latent autoimmune diabetes of adults (LADA) is also

stomach, whereas the posterior surface is in contact with

due to autoimmune β-cell destruction but the process is

the large vessels

(aorta, inferior vena cava and renal

slower than classical T1DM and occurs in an older age

vessels)

group

Physiology

The pancreas has an:

Box 13 Cells responsible for the endocrine

• Exocrine function: secretes hormones into the gastro-

function of the pancreas

intestinal system to help with food digestion

This function of the pancreas is discussed in the

• β-cells, producing insulin:

gastroenterology book of this series

Main hormone that maintains glucose homeostasis

• Endocrine function: the pancreas is the main organ

Secretion is triggered by high plasma glucose

Composed of two polypeptide chains linked by

that regulates blood glucose levels.

disulphide bridges

Derived from proinsulin, which is packaged in the

Pathophysiology

Golgi system of β-cells and transformed to the active

• Defects in insulin secretion and action result in the

form, insulin, by cleavage of C peptide by protease

development of diabetes mellitus

enzymes. Endogenous insulin production is associated

• Insulin deficiency is the pathophysiological abnormal-

with detectable C peptide levels in contrast to

ity in type 1 diabetes (T1DM)

administering exogenous insulin, which can be useful in

• Insulin resistance with consequent β-cell dysfunction

differentiating criminal or self-harm cases of insulin

are the pathophysiological abnormalities in most cases of

administration (raised insulin with undetectable C

type 2 diabetes (T2DM)

peptide levels) from endogenous insulin production

(raised insulin and C peptide levels)

• α-cells, producing glucagons (discussed in the

Diabetes mellitus

neuroendocrine section)

• This common disease is characterized by raised blood

• δ-cells, producing somatostatin (discussed in the

glucose

neuroendocrine section)

• PP cells, producing pancreatic polypeptide (discussed in

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

the neuroendocrine section)

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

The pancreas

Splenic artery

• Mitochondrial mutations

Hepatic artery

Left

adrenal

Genetic defect in insulin action:

Bile duct

Aorta

gland

Right

• Resulting in severe insulin resistance (very rare)

adrenal

Spleen

gland

Drug induced (<5%)

• Glucocorticoid treatment: particularly in those receiv-

ing high dose of steroids

• Thiazides

Pancreas

Gestational diabetes (<5%)

Right

Left

• Diabetes that occurs during pregnancy

kidney

Inferior

• Resolves spontaneously after giving birth

Duodenum

vena cava

• Associated with increased risk of macrosomic (large)

Figure 28 Anatomy of the pancreas.

babies

• Affected women are at high lifetime risk of developing

T2DM (up to one-third)

From the practical point of view, it is important to

Type 2 diabetes (75-85% of cases)

distinguish between type 1 and type 2 diabetes as failure

This is due to a combination of:

to initiate insulin in a type 1 diabetes patient may result

• Insulin resistance (usually as a result of obesity)

in death. This is fully discussed below.

• β-cell dysfunction: insulin resistance is compensated

for by an increase in insulin production by pancreatic β-

Clinical presentation

cells. Eventually, these cells get

‘worn out’ and their

There are a wide range of symptoms, including:

insulin production decreases to a level that is unable to

• Polyuria secondary to osmotic diuresis

compensate for insulin resistance, leading to high plasma

• Polydipsia or increased thirst

glucose and the development of diabetes

• Visual disturbances: due to changes in the lens, sec-

Type 2 diabetes is on the increase, mainly due to the

ondary to high glucose levels

increased prevalence of obesity and sedentary lifestyle

• Repeated skin infections

• Vaginal candidiasis

(thrush) is common in female

Secondary causes of diabetes (<5%)

subjects

• Pancreatic destruction

• Tiredness

Pancreatitis

• Weight loss (usually in type 1 diabetes)

Trauma

• The patient may present with associated complications

Pancreatic cancer

such as:

Cystic fibrosis

Myocardial infarction

Haemachromatosis (infiltration of the pancreas with

Stroke

iron)

Renal disease

• Endocrine disease

• In type 2 diabetes, the disease is commonly clinically

Acromegaly

silent and is discovered during investigations for other

Cushing’s syndrome

pathologies

During assessment of patients, it is important to dif-

Genetic defects (<5%)

ferentiate T1DM from T2DM as management of these

Genetic defect in insulin secretion:

conditions is entirely different (see Table 20). The follow-

• Maturity onset diabetes of the young (MODY)

ing should be taken into account:

An autosomal dominant condition

• Detailed history: patients with T1DM present with

A number of different types have been described, the

short history of symptoms (days to weeks), in contrast to

commonest are due to mutation in genes for hepatic

individuals with T2DM (months to years)

nuclear factor (HNF)1α, known as MODY 3, and glu-

• The presence of weight loss, particularly in a younger

cokinase, known as MODY 2

individual, suggests T1DM

Part 1: Basics

Table 20 Summary of the main features of type 1 diabetes (T1DM) and type 2 diabetes (T2DM).

T1DM

T2DM

Aetiology

Autoimmune

Insulin resistance and β-cell dysfunction

(β-cell destruction)

Peak age

12 years (can occur at any age)

60 years (increasingly seen at a young age due to obesity)

Prevalence

0.3%

Around 6%

Presentation Osmotic symptoms (days to weeks), weight loss, DKA

Osmotic symptoms (months to years), diabetic

complications

Patient usually slim

Patient usually obese

Treatment

Diet and insulin

Diet, exercise (weight loss), oral hypoglycaemic agents,

insulin later

DKA, diabetic ketoacidosis.

• Individuals with T1DM tend to be thin (but not

Diabetic hyperosmolar non-ketotic hyperglycaemia

always) and those with T2DM tend to be overweight (but

(HONK)

not always)

• A complication of T2DM, usually seen in the elderly

• Although rare, causes of secondary diabetes should be

• Characterized by high glucose levels and severe

kept in mind and appropriate investigations should be

dehydration

arranged if necessary

• Acidosis is usually absent

• The presence of a family history suggestive of an auto-

somal dominant condition, particularly in those with

Hypoglycaemia

diabetes at a young age, should alert to the possibility of

• This is discussed under the treatment of diabetes

MODY

below

• All patients

(particularly older subjects) should be

assessed for the presence of complications (macrovascu-

lar and microvascular complications, detailed below)

Chronic complications

Macrovascular (large vessel) complications

Complications of diabetes

Patients with diabetes are at high risk of cardiovascular

Acute complications

disease including:

Diabetic ketoacidosis (DKA)

• Ischaemic heart disease (IHD): all newly diagnosed

• DKA is due to the absence of insulin and, therefore, it

diabetes patients should be assessed for the possibility of

is mainly seen in patients with T1DM

IHD

• Not uncommonly, DKA is the first presentation of

History: chest pain or shortness of breath on

T1DM

exertion

• The absence of insulin results in switching from glucose

ECG: previous myocardial infarction, ischaemic

to fat metabolism (in order to provide energy), a pathway

changes

that is associated with accumulation of ketone bodies,

More sophisticated tests if in doubt (exercise test,

which cause metabolic acidosis

angiogram)

• Therefore, ketoacidosis is characterized by the pres-

• Cerebrovascular disease:

ence of:

History of weakness or slurred speech should alert

Acidosis (due to the accumulation of ketone bodies)

to the possibility of this diagnosis

Dehydration (due to osmotic diuresis and vomiting,

Any neurological signs will warrant further

see below)

investigations

The pancreas

• Peripheral vascular disease

• Random plasma glucose

History of pain in the legs on exertion

Levels above 11.0 mmol/L in the presence of symp-

Feel the foot pulses

toms confirm the diagnosis

• Oral glucose tolerance test

Microvascular (small vessel) complications

This should be performed in unclear cases

These include retinopathy, nephropathy and

Subjects are given 75 g glucose and plasma glucose

neuropathy.

is assessed at 0 min and 120 min

• Retinopathy: the following changes can be observed:

Individuals with 2-h glucose <7.8 mmol/L: diabetes

Background changes (minor changes): microaneu-

ruled out

rysms, small intraretinal haemorrhages

(dots) and

Individuals with 2-h glucose >11.1 mmol/L: diabetes

hard exudates due to the leakage of lipids

is confirmed

Preproliferative changes

(serious changes, need

Individuals with

2-h glucose

>7.8 and

<11.1:

attention): soft exudates

(areas of infarction), also

impaired glucose tolerance is present (a prediabetic

known as cotton wool spots, and intraretinal micro-

condition-risk of future diabetes is high)

vascular abnormalities (IRMA), tortuous and dilated

2. Differentiate between types of diabetes

looking vessels occurring as a result of retinal

• A careful history is probably the most important tool

ischemia

to differentiate between different types of diabetes

Proliferative changes

(very serious changes, need

immediate attention): new vessel formation

• Nephropathy

Microalbuminuria: excretion of small amounts of

Box 14 How to assess a newly diagnosed

albumin in the urine. This is an early stage of diabetic

diabetes patient

nephropathy, which can be reversible

Take a careful history

Macroalbuminuria: excretion of large amounts of

• Onset of symptoms: sudden (days/weeks) or gradual

albumin in the urine. This is seen in more advanced

(months or years)

stages

• Any history of weight loss

Raised urea and creatinine: indicates renal

• Any family history

failure

Autoimmunity: a personal or family history of

• Neuropathy

autoimmunity (thyroid disease, vitiligo, coeliac disease,

Peripheral: altered sensation in the feet, which pre-

etc.), should raise the possibility of T1DM

disposes to foot ulcers; Charcot’s osteoarthropathy,

Diabetes at a young age in an autosomal dominant

results in bone fractures and deformity and can be

fashion: should raise the possibility of MODY

difficult to diagnose and treat (Fig. 29, colour plate

• Check weight and body mass index (BMI): overweight

subjects are more likely to have T2DM

section); and neuropathy can also involve a main nerve

• Look for signs of secondary diabetes (Cushing’s

or a group of nerves (third nerve palsy for example),

syndrome, acromegaly, etc.)

causing sensory or motor abnormalities

• Check for the presence of complications (particularly in

Autonomic: can result in orthostatic hypotension,

those with suspected T2DM)

gastrointestinal symptoms (vomiting, diarrhoea), or

Macrovascular: chest pain or breathlessness on

erectile dysfunction

exertion; history of cerebrovascular accident (CVA) or

transient ischaemic attacks (TIA) (slurred speech, limb

Investigations

weakness); history of leg pain after exercise is suggestive

1. Confirm the diagnosis of diabetes:

of peripheral vascular disease; need to do a thorough

• Fasting plasma glucose

cardiovascular examination

Levels above 7.0 mmol/L in the presence of symp-

Microvascular: history of foot ulcers/swelling of the

joints (examine the feet and check sensation using

toms or two tests above 7.0 mmol/L in the absence of

monofilament test); history of visual abnormalities

symptoms confirm the diagnosis of diabetes

(examine the fundi for diabetic retinopathy); renal

• Subjects with fasting glucose >6.0 but ≤7.0 mmol/L are

disease is clinically silent in the early stages of the

labelled as having impaired fasting glucose and should

disease (check urine for microalbuminuria)

undergo a glucose tolerance test (see below)

Part 1: Basics

• Urine dipstick: this is an essential test in all diabetes

patients. The presence of heavy ketonuria is indicative of

T1DM. Ketonuria may also occur after prolonged

fasting

• Laboratory tests can be useful in difficult cases:

Anti-glutamic acid decarboxylase (GAD) and anti-

tyrosine phosphatase

(IA-2) antibodies: antibodies

against one or both molecules are present in around

Figure 30 Duration of insulin cover after actrapid injection (h).

80% of patients with T1DM. Their absence does not

rule out the diagnosis of T1DM

Genetic testing: in suspected MODY commonest are

mutations in HNF1α (MODY 3) and glucokinase

(MODY 2) genes

Cases with suspected secondary cause: ferritin levels

(haemachromatosis), CT abdomen in pancreatic

cancer, Cushing’s syndrome and acromegaly

3. Investigate for the presence of complications

• Acute

Figure 31 Duration of insulin cover after insulatard injection

If in doubt whether the patient has early DKA,

(h).

you can measure venous pH and bicarbonate (bicar-

bonate

<15 mmol/L with or without low pH is

working in 30 min and peaks at 2-4 h after injection,

diagnostic)

covers up to 6-8 h post injection (Fig. 30)

Do not miss the diagnosis of acute diabetic ketoaci-

Intermediate acting insulin or NPH insulin (Insula-

dosis, which may be fatal if not treated appropriately

tard): starts working in 2 h and peaks 8 h post injec-

• Chronic

tion, covers for 16-20 h (Fig. 31)

ECG: this should be done in all newly diagnosed

Mixtures: short and intermediate acting with varied

diabetes subjects as silent myocardial infarction is

proportions; humulin M1 (10% short and 90% inter-

common in this group of patients

mediate acting), humulin M3 (30% short and 70%

CT head and carotid Doppler: in case of history of

intermediate acting) (Fig. 32)

TIA

•

Analogue insulin preparations

Doppler of peripheral arteries: in case of history or

Ultra-short

(or ultra-fast) acting insulins

(lispro,

examination suggesting peripheral vascular disease

aspart, glulisine): start working almost immediately

Urinary microalbumin and U&Es to rule out

and peak at 1-2 h post injection and cover for around

nephropathy

4 h post injection

Nerve conduction tests: in the presence of atypical

Long acting insulins (glargine, detemir): relatively

neuropathic changes

flat profile (minimal peak, thus less chance of hypogly-

caemia), start working in 2 h and last 20-24 h post

injection

Treatment

Mixtures: ultra-short acting analogues with interme-

Treatment of type 1 diabetes (T1DM)

diate insulin. There are no mixtures with long acting

Patients with T1DM should be treated with insulin.

insulin analogues

There are different preparations of insulin, which are

briefly discussed here. At present, the main insulin prepa-

How to give insulin injections

rations in use are human insulin and insulin analogues.

There are a number of regimes that can be used in T1DM

Animal insulin preparations (bovine and pork) are very

but the most widely adopted are:

rarely used these days.

• Twice daily injections with mixture of insulins (i.e.

Types of insulin:

Novomix 30, Humulin M3, Humalog mix 25) (Fig. 33)

• Human insulin preparations

• Four daily injections of insulin: also called basal bolus

Short

(or fast) acting insulin

(Actrapid): starts

regime (Fig. 34)

The pancreas

10/90 mix

20/80 mix

30/70 mix

40/60 mix

50/50 mix

Figure 32 Duration of insulin cover after injection of different insulin mixtures (h).

Hours

Breakfast

Lunch

Evening

Sleep

Figure 33 Twice daily insulin injection regime for T1DM.

One injection of intermediate or long acting insulin

In T2DM patients:

(to cover basal insulin)

• Single injection of intermediate or long acting insulin

Three injections of short acting or ultra-short acting

can be added to existing oral hypoglycaemic agents

insulin with meals (bolus insulin)

• Above regimes (same as T1DM) can also be used if one

Basal bolus regime gives better flexibility and has a

injection of insulin is not controlling plasma glucose

lower risk of hypoglycaemic episodes

levels

Part 1: Basics

Long acting

insulin

Hours

Breakfast

Lunch

Evening

Sleep

Figure 34 Four daily injections of insulin for T1DM.

How to start a newly diagnosed T1DM patient

Lipoatrophy and lipohypertrophy at insulin injec-

on insulin?

tion sites: the former is rarely seen now but the latter

Newly diagnosed patients can be started on two or four

can still occur (Fig. 35, colour plate section). Further

injections of insulin after appropriate education, which

injection into affected areas should be avoided

is best done by the diabetes nurse specialist.

• Starting total 24-h dose of insulin is usually around

Other than daily injections, are there any other modes

0.3-0.6 unit/kg, divided into:

of delivery for insulin?

Half to two-thirds of the dose as intermediate/long

• Insulin can be delivered by an insulin pump, using a

acting insulin

cannula placed in the abdomen (changed every 2-3

One-third to half the dose as short acting insulin

days)

• A newly diagnosed patient weighing 70 kg can be

Insulin is continuously infused with bolus doses

started on:

given with meals

Mixture of insulin 12 units morning and 8 units

• Inhaled insulin

evening

An insulin preparation, which can be given through

Basal bolus: 8-10 units of intermediate/long acting

inhalation. It only substitutes short acting insulin and

and 2-6 units of fast/ultra-fast acting with meals

the patient still needs to inject the long or intermediate

• It is good practice to teach insulin-treated patients car-

acting insulin

bohydrate counting (assessment of carbohydrate in each

meal) to adjust the doses of insulin injections according

What to do with a T1DM patient during

to meal size

clinic reviews?

• Assess diabetes control

What are the complications of insulin treatment?

Review blood glucose diary, paying particular atten-

• Hypoglycaemia

tion to highs and troughs

All patients should be warned about the symptoms

Is there any particular pattern for the sugar readings?

of hypoglycaemia, which can be very unpleasant

For example, high fasting sugar indicates the need for

including: tremor, sweating, nausea and feeling

higher doses of intermediate or long acting insulin;

hungry

high post meal sugars indicate the need for higher

All patients should be properly educated to learn

short acting insulin before the meal

how to manage a hypoglycaemic episode (detailed

Check HbA1c, which gives an indication of the

below)

average diabetes control over the previous 6 weeks

The pancreas

• Check for associated complications

in the UK. These agents lower blood glucose by stimu-

Cardiovascular (particularly in older patients); check

lating pancreatic insulin secretion. Side effects include

blood pressure in all patients

hypoglycaemia and weight gain

Nephropathy (check urine for albumin excretion)

Meglitinides: natiglinide and repaglinide are the

Retinopathy

(regular retinal examination or

most widely used agents. These increase insulin secre-

photography)

tion by the pancreas, an effect that is more pronounced

Foot examination: pulses and peripheral sensation

after a meal. They are less commonly associated with

hypoglycaemia and weight gain compared with sul-

phonylureas. In practice, they are often less effective

Treatment of type 2 diabetes (T2DM)

reducing glucose levels compared with

• Education of patients is very important

sulphonylureas

• The importance of diet and exercise should be

• Insulin sensitizers

emphasized

Thiazolidinediones

(also known as glitazones),

• All patients should be reviewed by a dietician for

pioglitazone and rosiglitazone, are stimulators

appropriate advice

the

peroxisome

proliferators

nuclear

• Measures to induce weight loss (most of these patients

receptor

(PPAR)-γ, which results in improve-

are overweight) should be encouraged/implemented

ment in insulin resistance and decrease in blood

• In the initial phases of the disease diet and exercise may

sugar

be enough to maintain good diabetes control

These agents have cardiovascular protective

• Patients will eventually need medical intervention with

features

oral hypoglycaemic agents or insulin

Recent analysis, however, indicates that rosiglitazone

has a neutral effect on cardiovascular events, whereas

Oral hypoglycaemic agents

pioglitazone may reduce the risk

These have proliferated in the past decade or so and we

These agents can cause fluid retention and, there-

now have a number of different treatment options. These

fore, they are contraindicated in subjects with heart

include:

failure

• Biguanides (main agent is metformin)

These agents induce weight gain

The first-line agent in obese T2DM patients

• Drugs that interfere with glucose absorption

Metformin lowers blood glucose levels by: reducing

α-Glucosidase inhibitors (acarbose is perhaps the

hepatic glucose output (decrease in glycogenolysis),

most widely used agent in this group)

reducing glucose absorption and mildly reducing

Use of these agents in the UK is limited due to a

insulin resistance

modest blood glucose lowering effect and gastrointes-

Effective, cheap and safe

tinal side effects, mainly bloating, which are very

Use of this agent is associated with weight loss, which

common

is welcome in subjects with diabetes

• Agents working on the glucagon-like peptide-1

Side effects are mainly gastrointestinal

(nausea,

(GLP-1) system

bloating) and these are minimized by a gradual

New agents introduced in the UK in 2007

increase in drug dose or use of long acting

GLP-1 is a natural hormone secreted by the gastro-

preparations

intestinal tract in response to meals

Contraindications include: renal failure - if creati-

GLP-1 stimulates insulin secretion by the pancreas

nine is >150 μmol/L, the drug should be discontinued

and inhibits glucagon production, thereby lowering

(or not started) due to fears of inducing lactic acidosis;

plasma glucose levels

advanced heart or liver failure - again there is a risk of

GLP-1 has a very short half-life as it is metabolized

inducing lactic acidosis. Use of metformin in mild

by dipeptidyl peptidase (DPP)-4 enzymes and quickly

heart failure or minor derangement of liver function is

cleared from the circulation

perfectly safe

• GLP-1 analogues (exenatide)

• Insulin secretagogues

Work similarly to native GLP-1 but are slowly

Sulphonylureas: gliclazide, glibenclamide and

metabolized by DPP-4 enzymes, resulting in a longer

glimepiride are probably the most widely used agents

half-life in the circulation

Part 1: Basics

Table 21 The main features of the new hypoglycaemic

Rimonabant is a new agent for weight reduction

agents, DPP-4 and glucagon-like peptide-1 (GLP-1) analogues.

licensed for use in the UK in 2007. It is a cannabinoid

receptor type 1 (CB1) blocker and works at multiple

DPP-4

GLP-1 analogues

levels (see Table 22). It has a role in the management

of multiple cardiometabolic factors, e.g. improvement

Administration

Oral

Injections

in lipid profile, improvement in glycaemic control and

Efficacy

+++

reduction in central obesity. Side effects include

depression in up to 15% of treated individuals, and,

Weight

Neutral

Weight loss

therefore, this agent is contraindicated in those with a

Side effects

Little

15-20% (gastrointestinal)

history of depression or during treatment with

antidepressants

The mode of action and contraindications of each of

the antidiabetic agents is summarized in Fig. 36 and

Table 22 Site and mechanism of action of the cannabinoid

Table 23.

receptor blocker, rimonabant.

Site

Mechanism

When do we need to move patients from oral

hypoglycaemic treatment to insulin?

Hypothalamus

Decreases appetite

• Failure of oral hypoglycaemic agents to maintain ade-

quate glucose levels

(metformin is usually continued

Muscle

Increases glucose uptake

with insulin treatment)

Gastrointestinal tract

Increases satiety signals

• Pregnancy: insulin is safe to use during pregnancy and,

therefore, pregnant women with diabetes are usually

treated with insulin only

Injected s.c. twice a day resulting in a reduction in

• Severe illness or operation requiring hospital admis-

blood sugar levels and weight loss. Side effects includ-

sion: oral hypoglycaemic agents are temporarily stopped

ing gastrointestinal symptoms in relatively large

number of patients (around one-fifth), which may

Management of diabetic complications

improve with continued use of the drug

Acute complications

• DPP-4 inhibitors (sitagliptine/vildagliptine)

Diabetic ketoacidosis

Inhibition of DPP-4 results in slower breakdown of

• A medical emergency with a death rate of 3-5%

‘native’ GLP-1 and consequently an increase in plasma

• Is due to the lack of insulin and subsequent switch

levels

from glucose to fatty acid metabolism, which results in

These agents are less effective at reducing blood

the production of ketone bodies:

glucose levels compared with GLP-1 analogues

Acetoacetic acid

DPP-4 inhibitors are weight neutral

Hydoxybutyric acid

They have advantages over GLP-1 analogues in that

Acetone

(giving DKA patients acetone-smelling

they are given orally (no injections are needed) and

breath)

side effects are minimal

• Subjects with DKA have three fundamental

Table

21 summarizes the main characteristics of

abnormalities

GLP-1 analogues and DPP-4 inhibitors.

Metabolic acidosis, which causes abdominal pain

• Slimming tablets

and vomiting, and compensatory hyperventilation

Orlistat inhibits intestinal lipase thereby reducing fat

(Kussmaul respiration): blowing off CO₂ results in

absorption. It is important to comply with a low-fat

respiratory alkalosis, trying to compensate for the

diet whilst on treatment with this agent, otherwise it

metabolic acidosis

may cause an oily (pretty unpleasant) diarrhoea

Dehydration, secondary to osmotic diuresis (high

Sibutramine is central appetite suppressant, which

glucose levels) and vomiting

may induce tachycardia and high blood pressure

Electrolyte imbalance, including hyperkalaemia, sec-

(regular monitoring is mandatory). This can be a

ondary to metabolic acidosis, hyponatraemia and

problem in hypertensive patients with diabetes

‘relative’ hypokalaemia due to vomiting

The pancreas

Biguanides

(metformin)

Muscle

Thiazolidinediones

Figure 36 Mode of action of different

oral hypoglycaemic agents. The

Adipose

biguanide metformin reduces hepatic

tissue

glucose uptake and has a mild insulin

DPP-4

Liver

sensitizing effect. Thiazolidinediones

inhibitors

reduce insulin resistance, making

Inactive

Pancreas

GLP-1

insulin more effective at reducing

blood sugar. Sulphonylureas and

DPP-4

Insulin

Stomach

meglitinides stimulate pancreatic

insulin secretion. GLP-1 analogues

have a similar effect to GLP-1 (increase

Glucose

insulin and reduce glucagon secretion),

GLP-1

but are slowly degraded by DPP-4

enzymes. DPP-4 inhibitors interfere

with GLP-1 degradation resulting in

Sulphonylureas and

increased levels of this hormone. α-

GLP-1

meglitinides

analogues

Glucosidase inhibitors reduce glucose

Gut

α-glucosidase

absorption.

inhibitors

Table 23 Main side effects and contraindications of agents used to control blood sugar levels in individuals with T2DM. Pregnant

women with diabetes should be treated with insulin and oral hypoglycaemic agents are generally contraindicated.

Agent

Side effects

Contraindication

Metformin

Gastrointestinal (bloating, diarrhoea)

Renal failure (even if mild)

Advanced heart and liver failure

Pregnancy (relative contraindication)

Sulphonylureas

Hypoglycaemia

Pregnancy

Weight gain

Thiazolidinediones

Fluid retention

Heart failure

Weight gain

Pregnancy

GLP-1 analogues

Gastrointestinal

Pregnancy

DPP-4 inhibitors

Rare

Pregnancy

Orlistat

Diarrhoea

Pregnancy

Sibutramine

Hypertension

Uncontrolled hypertension

Tachycardia

Pregnancy

Rimonabant

Depression

History or current treatment of depression

Pregnancy

Part 1: Basics

• Causes of DKA:

•

Fluid

New diagnosis of T1DM in 20% of cases

Fluid replacement usually starts with normal saline

In a known diabetic patient, DKA can be due to:

(0.9%): 1 L over the first h, 1 L over 2 h, then 1 L every

infection in 35% of cases, non-compliance with insulin

4-6 h, with careful monitoring of the patient and

injection in 30%, and errors in insulin administration

adjustment of fluid replacement accordingly. Normal

and dose calculation in 15%. In older patients, DKA

saline should be substituted with 5% dextrose infusion

may be precipitated by an ischaemic event such as

once plasma glucose drops below

12-15 mmol/L

myocardial infarction

(different protocols use different cut-offs)

•

Potassium

Clinical presentation of DKA

Failure to replace potassium can result in severe

DKA subjects can present with a variety of symptoms:

hypokalaemia, which may cause cardiac arrhythmias,

• Gastrointestinal

potentially resulting in death. Serum potassium is

Nausea

usually elevated on initial presentation due to the pres-

Vomiting

ence of acidosis, despite low total body potassium.

Abdominal pain

Potassium levels quickly drop after initiation of DKA

• Generally feeling unwell

treatment, as both insulin replacement and correction

• Coma in advanced cases

of acidosis shift the potassium from the extracellular

• In those with known diabetes, DKA should be

space into the cells. As a rough guide, 20 mmol/L

suspected in anyone who is not feeling or looking

potassium should be added to the fluid in patients with

well

normokalaemia, 40 mmol/L to those with hypokalae-

• In subjects with suspected DKA who are not known to

mia and no potassium should be given to those with

have diabetes, a proper history is paramount to make the

hyperkalaemia. Monitoring potassium levels

(every

correct diagnosis

2-4 h) during treatment is extremely important

•

Insulin

Investigations in suspected DKA

Insulin is started as an i.v. infusion at around 0.1 u/

These consist of:

kg/h and adjusted according to a sliding scale insulin

• 1. Confirm the diagnosis

(see Table 24). Capillary glucose should be checked

Raised glucose levels: glucose can be only slightly

hourly and i.v. insulin should only be stopped once the

elevated

urine is ketone-free and the patient is clinically well

Reduced plasma bicarbonate levels with or without

•

Bicarbonate

low pH (bicarbonate <15 mmol/L confirm the diag-

This is very rarely given; only in cases of severe aci-

nosis of DKA)

dosis not responding to conventional treatment. Bicar-

Presence of ketonuria

bonate administration should only be done in an

• 2. Rule out precipitating cause:

intensive care setting and after the involvement of a

Chest X-ray (? infection)

senior colleague with expertise in DKA management

Check urine for the possibility of infection

ECG (? myocardial infarction)

Table 24 An example of sliding scale insulin. This is only a

Take blood and urine samples for culture

guide and different sliding scales can be used as some

Note that a high white cell count may occur in sub-

individuals require higher doses of insulin whereas others need

jects with DKA in the absence of infection

less.

Treatment of DKA

Capillary glucose

Insulin dose

This should be promptly started and consists of fluid and

insulin replacement as well as management of electrolyte

<4.0 mmol/L

0.5 units/h (with i.v. dextrose): review

imbalance. In addition, treatment should be directed to

4.1-10.0 mmol/L

2 unit/h

the precipitating cause (if any). Monitoring of patients

after initial treatment is very important and local hospital

10.0-16.0 mmol/L

4 units/h

guidelines for the management of these patients should

>16.0 mmol/L

6 units/h: review

be strictly followed.

The pancreas

Type of fluid

Amount of fluid

Venous potassium

Potassium in i.v. fluid

Initially normal saline,

give 1 L over 1 hour, 1L over 2 hours,

>5.5 mmol/L

No potassium in IV

Once glucose <12-15 mmol/L switch

1L over 4 hours, then 1L 6 hourly,

3.5-5.5 mmol/L

20 mmol potassium/L

to 5% desxtrose

Modify according to clinical response

<3.5 mmol/L

40 mmol potassium/L

Bicarbonate is not usually used in DKA.

ELECTROLYTES It may be needed if acidosis not responding.

FLUID

DO NOT give bicarbonate without discussion

with a specialist with an expertise in DKA

management

Culture blood, urine and sputum

Only for high risk patients

DKA

?PRECIPITANT

CXR and ECG (and review!)

ANTICOAGULATION

MANAGEMENT

(Clexane 40 mg s.c.)

Broad spectrum antibiotics

(if infection cannot be ruled out)

MONITORING

INSULIN

Check venous glucose, bicarbonate and potassium at:

Capillary glucose (BM)

Insulin

0, 2, 4, 8 and 24 hours

<4.0 mmol/L

0.5 units/hr (plus i.v. dex.)

Review the results and the patient and act!

4.1-10.0 mmol/L

2.0 units/hr

Modify monitoring according to results and

10.1-16.0 mmol/L

4.0 units/hr

clinical condition.

> 16.0 mmol/L

6.0 units/hr

Please note that above tables are only guidelines and insulin infusion rate may need

modification. Continue i.v. insulin/dextrose until urine is ketone-free.

Figure 37 Summary of the management of diabetic ketoacidosis.

• Precipitating cause(s)

• Mortality is very high approaching

50% in these

Around two-thirds of DKA cases are due to

patients

newly diagnosed type

1 diabetes or compliance

• Causes include:

problems/errors in insulin administration in known

Omission of oral hypoglycaemic agents or insulin

diabetic patients. In around one-third, DKA is due

(rarely it can be the first presentation of T2DM)

to other causes such as infection or myocardial

Infection

infarction and these conditions should be treated

Vascular events such as myocardial infarction and

appropriately

stroke

• Other measures

Some recommend low-dose heparin to prevent

Clinical presentation of HONK

thromboembolism, but there is no clear evidence to

• Insidious onset of symptoms with ill health for weeks

support this practice, which is perhaps unnecessary

• History of osmotic symptoms

unless other risk factors exist (prolonged immobility)

• Symptoms of precipitating cause

A nasogastric tube may need to be inserted in those

• Coma

with severe vomiting or in those with impaired con-

scious level

Investigations in HONK

• Monitoring

• Glucose levels: these are usually very high

Capillary glucose should be checked hourly and

• U&Es, this usually shows high urea and creatinine

blood samples should be taken every 2-4 h for U&Es,

levels, with a relatively larger impairment in urea (pre-

bicarbonate and venous glucose. The clinical condition

renal renal failure)

of the patient should be regularly assessed

• There is no acidosis in these patients (unless it is due

The management of DKA is summarized in Fig. 37.

to the precipitating cause)

• Investigations for causes of HONK are mandatory

Hyperosmolar non-ketotic hyperglycaemia (HONK)

(CXR, ECG, urinalysis, CT head if necessary)

• This is characterized by the gradual development of

• Blood and urine cultures should be requested in all

hyperglycaemia

patients with HONK

Part 1: Basics

Treatment of HONK

• Patients with hypoglycaemic symptoms should have

Treatment of HONK is broadly similar to that of DKA,

their capillary glucose checked to confirm the diagnosis

but with some differences:

before initiating treatment

•

Fluid

• Patients with frequent hypoglycaemic episodes may

Fluid replacement should be more gentle in HONK

lose their warning symptoms, in which case plasma

compared with DKA as these are older patients, who

glucose should be kept slightly elevated for 2-3 weeks in

are more prone to heart failure with aggressive fluid

order to regain the hypoglycaemic symptoms

replacement. In difficult cases, a central line should be

inserted to help guide the appropriate fluid

Treatment of hypoglycaemia

replacement

• Patient conscious:

•

Potassium

Oral glucose or sucrose (any fluid high in sugar

In uncomplicated HONK, potassium levels do not

content would do, such as Lucozade)

drop particularly quickly due to the absence of acido-

• Patient unconscious

sis, but this should still be carefully monitored

Intravenous glucose

•

Insulin

Intramuscular or s.c. glucagons (this loses its effect

Despite the very high glucose levels in these patients,

with repeated dosing)

insulin requirements in HONK are modest and, there-

fore, insulin should be given at 0.5-2 units/h aiming

Chronic complications

for a gradual drop in blood sugar

(around

Investigations for chronic complications have been dis-

5 mmol/L/h)

cussed above and only treatment is covered here.

•

Bicarbonate

This is not needed in uncomplicated hyperosmolar

Treatment of microvascular disease

hyperglycaemia as the patient is not usually acidotic

•

Retinopathy

•

Precipitating cause(s)

Ensure good glucose control

Infection is the most common precipitating cause

Ensure good blood pressure control

and, therefore, antibiotic cover must be started after

Laser therapy in advanced stages

appropriate cultures

•

Nephropathy

•

Other measures

Early nephropathy (microalbuminuria): angiotensin

Due to high osmolarity and dehydration, throm-

converting enzyme inhibitors or angiotensin receptor

botic complications are very common and, therefore,

blockers (sometimes a combination of the two) can be

all patients should be covered with prophylactic

used to delay/prevent further deterioration in renal

unfractionated heparin

function. Also, need to ensure good glycaemia and

•

Monitoring

blood pressure control

This should be done regularly with blood samples

Advanced nephropathy

(macroalbuminuria or

taken every 2 h in the first 6-8 h to assess response to

raised creatinine): similar measures to those above can

treatment

be used. Potassium and renal function should be fre-

quently monitored and referral to a renal physician

Hypoglycaemia

considered

This is fully discussed in the neuroendocrine section of

End-stage renal disease: dialysis and renal

this book and, therefore, it will only be addressed here in

transplant

relation to diabetes.

•

Neuropathy

• Hypoglycaemia in diabetes patients may be secondary

Painless peripheral neuropathy: repeated foot exam-

to oral hypoglycaemic agents (usually sulphonylurea) or

ination by patient and/or cohabiting relative and

insulin

regular chiropody

• All patients with diabetes should be warned regarding

Charcot’s arthopathy: immobilization of the joint is

hypoglycaemic symptoms:

important to prevent further damage, and bisphos-

Tremor and sweating

phonate may be of help

Nausea

Painful peripheral neuropathy: difficult to treat and

Hunger

most only have a partial response. Some of the agents

The pancreas

used include: tricyclic antidepressants, capsaicin, anti-

T2DM diabetes is similar to those without diabetes and

convulsants (phenytoin, gabapentin) and opiates

a previous cardiac event

Autonomic neuropathy: postural drop in blood

• Patients with diabetes and established cardiovascular

pressure can be treated with mechanical measures

disease are treated similarly to high risk non-diabetic

(wearing support stockings, sleeping with the head

individuals with known cardiovascular disease (discussed

elevated) and fludrocortisone (monitor for hyperten-

in the cardiovascular book of this series)

sion and hypernatraemia). Gastrointestinal symptoms

• Diabetes patients should, therefore, be treated with:

such as vomiting can be treated with metoclopramide,

Lipid lowering agents such as statins (simvastatin,

domperidone and erythromycin, and diarrhoea with

atorvastatin, rosuvastatin) to lower cholesterol levels

loperamide

and reduce cardiovascular events.

Sexual dysfunction: rule out an endocrine cause.

Other agents can also be used such as ezetimibe,

Phosphodiesterase inhibitors, such as sildenafil, may

which inhibits cholesterol absorption in the gut, and

help. Ensure good diabetes and blood pressure

fibrates, which lower cholesterol levels but their main

control

effect is on triglycerides

Angiotensin converting enzyme inhibitors (ACEI)

Treatment of macrovascular complications

Antiplatelet agents (aspirin or clopidogrel)

• The majority of patients with diabetes die of cardio-

Agents to maintain strict blood pressure control

vascular disease

Treat microalbuminuria, which is a cardiovascular

• The risk of myocardial infarction in subjects with

risk

Lipid abnormalities and obesity

Lipid abnormalities

Diabetes mellitus: mainly affects triglyceride levels

• The two main lipid molecules in the plasma are triglyc-

(increase) and HDL levels (decrease), particularly in

erides and cholesterol

those with poor glucose control

• To make these lipid particles water-soluble, they are

Hypothyroidism: affects LDL levels (increase)

bound to phospholipids and lipoproteins in plasma

Renal failure: affects LDL levels

(increase), HDL

• Lipid measurements are best performed on a fasting

(decrease) and triglycerides (increase)

sample. The following measurements can be done:

Liver disease: obstructive liver lesions affect LDL

Total cholesterol (TC) high levels are atherogenic.

levels (increase)

TC is composed of low-density lipoprotein cholesterol

Drugs: a number of drugs can affect lipid levels

(LDLc) - high levels are associated with increased risk

including β-blockers, thiazide diuretics, steroids, pro-

of vascular disease - and high-density lipoprotein cho-

tease inhibitors and alcohol

lesterol

(HDLc) - low levels are associated with

increased risk of vascular disease, whereas high levels

Clinical presentation

are protective

• Patients may be asymptomatic and hyperlipidaemia is

Triglycerides: high levels are atherogenic and can

picked up during routine testing

also result in pancreatitis

• Others can present with complications of hyperlipi-

daemia including:

Hyperlipidaemia

Atherothrombotic disease

(myocardial infarction,

There are a number of different types of hyperlipidae-

stroke)

mias, including:

Pancreatitis

• Isolated raised cholesterol

• Individuals with secondary hyperlipidaemia present

Polygenic hypercholesterolaemia: probably the com-

with symptoms of original disease

monest cause of isolated hypercholesterolaemia

Familial hypercholesterolaemia: an autosomal dom-

Treatment

inant condition affecting 1 : 500 people

• Lifestyle changes are important

(diet, exercise and

• Isolated raised triglycerides

stopping smoking) as these simple measures can lower

Autosomal dominant affecting around 1 : 300 people,

LDL and increased HDL levels

characterized by eruptive xanthomas and pancreatitis

• For primary prevention (individuals with no previous

• Raised cholesterol and triglycerides

complications due to hyperlipidaemia): there are special

Familial combined hyperlipidaemia: occurs in 1 : 250

risk factor engines that calculate future cardiovascular

people

risk and hyperlipidaemic agents are usually used in those

• Secondary causes of hyperlipidaemia

with more than 20% risk over a 10-year period

Diet excessive in fat

• Individuals with a previous vascular event or high-risk

subjects (for example diabetics), are treated with hyper-

lipidaemic agents even in the presence of normal lipid

profile

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

• Agents used include statins, such as simvastatin, ator-

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

vastatin and rosuvastatin

Lipid abnormalities and obesity

Most widely used hyperlipidaemic agents due to

Cardiovascular disease

their undoubted clinical benefits

Hypertension

Mode of action is related to decreased synthesis of

Mechanical joint pain and osteoarthritis

cholesterol in the liver [inhibition of

3-hydroxy, 3-

Sleep apnoea

methylglutaryl coenzyme A (HMG CoA)]

Increased risk of cancers

Effective at reducing LDL levels, minor effect on

Reproductive abnormalities

(PCOS, impaired

HDL and triglycerides

fertility)

Side effects are rare and include muscular aches and

pains, derangement in liver function and rhabdomy-

Clinical presentation

olysis, a potentially life-threatening complication but

• Concerns over body image secondary to obesity

fortunately very rare

• Complications (e.g. diabetes, cardiovascular disease)

All diabetes patients above the age of 40 are prescribed

a statin (regardless of cholesterol levels), to reduce the

Box 15 Obesity and BMI

risk of future vascular events

Ezetimibe

• Obesity is assessed using body mass index (BMI),

This agent reduces cholesterol absorption

calculated by the formula: weight (kg)/[height(m)]²

Effective in combination with a statin but less

• BMI = 18.5-24.9: healthy

impressive when used alone

• BMI = 25-30: overweight

• Fibrates

• BMI >30: obese

Effective at reducing triglycerides and, to a lesser

extent, LDL levels. Also, they raise HDL levels

Investigations

Their role in reducing cardiovascular risk is not as

• Fasting glucose (rule out diabetes)

clear as statins

• Fasting lipid profile

Usually used as second- or third-line treatment,

• Thyroid function tests

except in those with isolated hypertriglyceridaemia,

• ECG

when fibrates are used as first-line treatment

• Specific tests in case of clinical suspicion

(such as

• Nicotinic acid

Cushing’s syndrome for example)

Very effective at increasing HDL levels

The role of this agent in cardiovascular protection is

Treatment

unknown

• Lifestyle changes

Use is limited by side effects (severe flushing)

Diet: it is always useful to arrange an appointment

• Omega-3 fatty acids

with a dietician as minor changes in dietary habits can

Effective at reducing triglyceride levels

have a major influence on weight reduction

Increase exercise activity

Obesity

• More severe dietary restrictions: those with severe

• A major health problem in the developed world and it

obesity are sometimes admitted to hospital to initiate a

is on the increase

very low calorie diet under clinical supervision

• Related largely to increased food intake and sedentary

• Drug treatment

lifestyle

Orlistat inhibits gut lipase activity and reduces fat

• Genetic factors play a role as some individuals are

absorption. Patient should comply with low-fat diet.

more susceptible to developing obesity

Side effects include diarrhoea (oily diarrhoea is char-

• There are some rare cases of obesity that have a clear

acteristic), often in those who do not comply with

genetic basis (monogenic obesity), including:

reduction in fat intake

Leptin and leptin receptor deficiency

Sibutramine is a centrally acting appetite suppres-

Prader-Willi syndrome

sant. Side effects include hypertension and increased

Laurence-Moon-Biedl syndrome

heart rate, which limit its use

• Complications of obesity include:

Rimonabant is a newer agent which acts on the

Insulin resistance and diabetes mellitus

cannabinoid receptor blocker resulting in reduced

Lipid abnormalities

appetite, increased feeling of satiety, positive effect on

The neuroendocrine system

• Neuroendocrine cells are found in the gastrointestinal

• 72-h fast: this may be necessary in suspicious cases

tract

Patient is admitted to hospital and fasted

• Benign and malignant tumours of the neuroendocrine

Blood glucose and patient symptoms are regularly

system are rare and result in excess hormone production.

monitored

Clinical manifestations differ according to the nature of

The presence of low glucose (<2.5 mmol/L) together

the secreted hormone

with elevated insulin and C peptide confirms the

• It should be noted that some of these tumours may

diagnosis

also secrete pure endocrine hormones such as ACTH,

It is important to measure C peptide to rule out

PTH and GHRH resulting in Cushing’s syndrome,

exogenous administration of insulin (injected insulin

hypercalcaemia and acromegaly respectively

has no C peptide, whereas endogenous insulin produc-

• The characteristics of neuroendocrine tumours are

tion is associated with detectable plasma levels of C

summarized in Table 25

peptide)

Localizing the tumour

Insulinomas

• This can be difficult as tumours are often small

• Insulinomas result in hypoglycaemia through exces-

CT or MRI of the pancreas

sive secretion of insulin

Endoscopic ultrasound of the pancreas

• These are usually benign and only around 10% show

Radiolabelled octreotide scanning: the majority of

evidence of malignancy

these tumours take up octreotide

• May be part of MEN-1 (see below)

Treatment

Clinical presentation

• Surgical removal is the treatment of choice

• Symptoms of hypoglycaemia

(usually relieved by

• Octreotide and/or diazoxide can be useful to reduce

eating)

insulin secretion

Tremor and sweating

• Malignant tumours with metastases: palliative treat-

Nausea

ment with streptozotocin or 5-fluorouracil

Hunger

Weight gain secondary to frequent snacking

(to

Carcinoid tumours

avoid/treat hypoglycaemia)

• The majority of these tumours develop in the gut but

a minority can be found in the lungs and rarely other

Investigations

organs

Fasting tests

• These tumours produce mainly serotonin (which is

• 16-h fast: the absence of hypoglycaemia after 16-h fast

metabolized to 5-hydroxyindolacetic acid, 5HIAA)

makes the diagnosis of insulinoma unlikely (test to be

• These tumours also have the ability to produce a large

repeated three times)

number of other hormones and proteins including

ACTH, PTH, histamine and prostaglandin

• Carcinoid tumours are malignant but usually slow-

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

growing and some patients live 20-30 years after the

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

diagnosis

Part 1: Basics

Table 25 Characteristics of the neuroendocrine tumours.

Treatment

• Surgical removal

Excess hormone

Produced by

Clinical disease

• Somatostatin analogues for residual disease or if

surgery is contraindicated

Insulin

Pancreatic β-cells

Insulinoma

• Palliative therapy

Serotonin, kinins

Intestine

Carcinoid

Hepatic

embolization:

using

angiography

syndrome

techniques

Stomach

Chemotherapy: streptozotocin and 5-fluorouracil

Pancreas

Immunotherapy: α-interferon: useful in controlling

Gastrin

Pancreatic G cells

Gastrinoma

symptoms and can be combined with octreotide

(Zollinger Ellison

Stomach

syndrome)

Gastrinomas

Small intestine

• Two-thirds of these tumours are malignant

Glucagon

Pancreatic α-cells

Glucagonoma

• Excessive gastrin secretion results in increased acid

secretion by the stomach

Somatostatin

Pancreatic δ-cells

Somatostatinoma

Stomach

Clinical presentation

• Recurrent peptic ulcer disease that is refractory to

Small intestine

treatment

Vasoactive intestinal

Pancreatic VIP cells

VIPoma

• Malabsorption and diarrhoea

peptide (VIP)

Investigations

Clinical presentation

• Inappropriately elevated gastrin levels in the presence

• Flushing, can be precipitated by:

of increased stomach acid secretion confirms the

Alcohol

diagnosis

Spicy food

• Imaging

Exercise

As described under insulinoma

Carcinoid flush usually affects the face and upper

thorax and is shown in Fig. 38 (colour plate section)

Treatment

• Diarrhoea

• Surgical removal is the treatment of choice

• Asthma

• Proton pump inhibitors (omeprazole, lansoprazole)

• Right valvular heart lesions: fibrosis of right heart

for those with residual tumour or in whom surgery is

valves, which may be due to serotonin

contraindicated

• Pellagra-like skin lesions (excessive tryptophan metab-

olism results in nicotinamide deficiency)

Glucagonomas

It should be noted that individuals with carcinoid syn-

• Two-thirds of these tumours are malignant but they

drome due to gastrointestinal tumours will only be

are slow-growing

symptomatic if they have liver metastases, in contrast to

bronchial carcinoid subjects, who develop the symptoms

Clinical presentation

before metastases have taken place.

• Skin rash: necrolytic migratory erythema, can precede

the diagnosis by many years

Investigations

• Glucose intolerance and diabetes: due to excess gluca-

• Urinary 5-HIAA levels are elevated in the majority of

gon secretion

patients and have a high specificity

• Mucous membrane involvement: stomatitis and

• Plasma chromogranin A: higher sensitivity than 5-

glossitis

HIAA but lower specificity

• Imaging

Investigations

CT/MRI of chest and/or abdomen

• Raised plasma glucagon in the presence of symptoms/

Octreotide scanning

signs is diagnostic

The neuroendocrine system

• Localization

Table 26 Summary of the clinical presentation of different

CT or MRI of the abdomen

neuroendocrine tumours.

Octreotide scanning: particularly useful to evaluate

Neuroendocrine tumour

Clinical presentation

the extent of metastases

Insulinoma

Symptoms of hypoglycaemia

Treatment

• Surgery: cure rate is unfortunately very low (<10%)

Weight gain

• Octreotide or long acting somatostatin analogues can

Carcinoid syndrome

Flushing

be very useful to control symptoms

Diarrhoea

• Palliative

treatment with streptozotocin or

5-fluorouacil

Asthma

Right-sided heart lesions

Somatostatinomas

Pellagra-like skin lesions

• These are very rare with an incidence of

1 in 40

million

Gastrinoma (Zollinger Ellison

Recurrent and refractory peptic

• Characterized by:

syndrome)

ulcer disease

Glucose intolerance and diabetes mellitus

Glucagonoma

Typical skin rash (necrolytic

Gall stones

migratory erythema)

Diarrhoea and malabsorption

Glucose intolerance

VIPoma

Somatostatinoma

Glucose intolerance

• Very rare and characterized by:

Gall stones

Watery diarrhoea

Hypokalaemia

Diarrhoea and malabsorption

VIPoma

Watery diarrhoea

Neuroendocrine syndromes

These describe the association of a number of neuroen-

docrine abnormalities and include:

Some patients may have mucosal neuromas and

• Multiple endocrine neoplasia type 1

a marfanoid habitus and these are classified as MEN

An autosomal dominant condition (gene on chro-

2B.

mosome 11, menin gene is affected), with a prevalence

• Von Hippel-Lindau disease

of 1 in 10 000

An autosomal dominant condition

Tumours occur in two or more endocrine glands:

Clinical manifestations include: pheochromocy-

parathyroid

(hyperplasia or adenoma), almost all

toma, bilateral in half the patients; pancreatic neuro-

cases; pancreas

(insulinoma, gastrinoma),

70% of

endocrine tumours; retinal and central nervous system

patients; pituitary (prolactinoma, acromegaly), 30% of

hemangiomas; and renal cell carcinoma (the usual

patients. The easiest way to remember this is PPP

cause of death in these patients)

(parathyroid, pancreas, pituitary)

• Neurofibromatosis (NF)

• Multiple endocrine neoplasia type 2

NF1 is an autosomal dominant condition character-

An autosomal dominant condition (gene of chro-

ized by: multiple neurofibromas, café-au-lait spots, iris

mosome 10, ret protooncogene is affected)

lisch nodule, pheochromocytoma and gut endocrine

Around one-third of gene carriers do not manifest

tumours

clinically significant disease

NF1 should be differentiated from NF2, which is

Tumours occur in two or more endocrine glands:

characterized by: disorders of the central nervous

thyroid gland (medullary thyroid cancer), often the

system (meningiomas), cranial nerve tumours (usually

presenting feature; adrenal glands (pheochromocyto-

optic glioma); NF2 is not associated with endocrine

mas), in 50% of patients; parathyroid glands, in 30%

abnormalities

of patients. The way to remember this is TAP (thyroid,

The main clinical characteristics of the neuroendo-

adrenal, parathyroid)

crine tumours are summarized in Table 26.

Case 1

A 19-year-old with abdominal pain

and vomiting

Kathryn, a 19-year-old student, who is usually fit and well, is

What clinical features are associated

admitted to accident and emergency (A&E) with a 2-day

with weight loss?

history of abdominal pain, vomiting and feeling generally

• Chronic infections and infestations: particularly in

unwell. She has lost 5 kg in weight over the past 3 weeks

individuals with a deranged immune system, such as

for no clear reason. There is no significant past medical

patients with AIDS

history of note except for three episodes of urinary tract

• Malignancy

infection (UTI) over the past 6 months.

• Diabetes mellitus

• Hyperthyroidism

What are the differential diagnoses of

• Malnutrition: uncommon in Western countries

abdominal pain and vomiting?

• Degenerative neurological and muscular diseases

Intra-abdominal pathology

It is impossible to give an accurate diagnosis at this

• Peptic ulcer disease

stage and a more detailed history and careful physical

• Pancreatitis

examination is of paramount importance in order to

• Cholecystitis and gall stones

establish the correct diagnosis.

• Appendicitis

• Ectopic pregnancy

What questions will you ask?

• Intestinal obstruction

• Has the pain and vomiting started recently or has it

• Renal calculi and pyelonephritis

been occurring for weeks, months or years?

• Was the onset of pain sudden or gradual?

Other conditions associated with abdominal

• What is the pain like and how severe is it?

pain but less likely to cause vomiting

• Where is the pain localized?

• Dysmenorrhea

• Does anything relieve the pain?

• Pelvic inflammatory disease

• Has a new treatment been introduced recently?

• Inflammatory bowel disease

• Are there any associated symptoms

(review of

• Intra-abdominal arterial and venous thrombosis

systems)?

• Ruptured aortic aneurysm (in older individuals)

On further questioning, Kathryn tells you that the abdominal

Endocrine causes of abdominal pain and

pain was gradual in onset over 4-6 h, generalized and

vomiting

cramp-like, with severity varying between 2/10 and 4/10.

• Diabetes mellitus

complicated by diabetic

Nausea and vomiting preceded the abdominal pain by 6 h or

ketoacidosis

so. Kathryn has been on oral contraceptive pills (OCP) for 18

• Hypoadrenalism

months and her last withdrawal bleed was 1 week ago.

• Hypercalcaemia

Does this help with the diagnosis?

• The gradual onset of pain and low severity (although

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

this is subjective) make a surgical cause for the pain less

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

likely, but do not fully rule it out. For example, appendi-

Case 1

citis may initially present with gradual and cramp-like

Nausea

abdominal pain. Also, it should be noted that in some

Vomiting

cases of acute abdomen, the symptoms may be relatively

Abdominal pain

mild and this can be seen in older patients or in individu-

Associated symptoms: a few days/weeks history of

als who are on steroid treatment

polyuria and polydipsia (known as osmotic symp-

• The combination of OCP use and a recent normal

toms), and weight loss

withdrawal bleeding rules out dysmenorrhea and ectopic

The family history of autoimmunity further supports

pregnancy as causes for Kathryn’s pain

this diagnosis, as it suggests a genetic predisposition to

autoimmune disease in Kathryn

During review of systems and on further questioning,

Kathryn tells you that she had polyuria up to 15 times/day

Kathryn deteriorates and becomes slightly confused, with a

and nocturia 6 times/night for 2 weeks prior to her current

drop in her Glasgow Coma Scale (GCS) from 15/15 to 13/15

presentation. She is a non-smoker and drinks up to 20 units

(E3, V5, M5). On examination, she is tired, dehydrated,

of alcohol per week. Family history includes pernicious

tachycardic at 112 beats/min, has a temperature of 36.6°C,

anaemia in her uncle and hypothyroidism in her mother.

blood pressure of 115/70 mmHg, with a postural drop of

20/10 mmHg, and respiratory rate of 32/min, with otherwise

Does this help with the diagnosis?

normal chest examination. Cardiac auscultation is normal,

Polyuria can be secondary to a number of causes. In this

and abdominal palpation reveals minimal generalized

case, a urinary tract infection may have caused the

tenderness with no rigidity, guarding or rebound tenderness.

abdominal pain and polyuria, which is usually associated

with dysuria, and only small amounts of urine are passed

How do her clinical findings help with

on each occasion.

the diagnosis?

• Kathryn is clinically dehydrated with tachycardia and

a postural drop in blood pressure indicating significant

Box 16 Other causes of polyuria

fluid loss

• The tachypnea is a matter of concern and could be due

• Electrolyte abnormalities such as hypercalcaemia

• Chronic renal disease

to a primary lung pathology or secondary causes. A

• Endocrine disease such as diabetes insipidus (lack of, or

primary lung pathology in this patient may be:

ineffective, antidiuretic hormone)

Chest infection may result in tachypnea and pneu-

• Osmotic diuresis due to high plasma glucose levels

monia is a recognized cause of abdominal pain.

(diabetes mellitus)

However, she is apyrexial and chest auscultation is

• The use of drugs such as lithium and demeclocycline

unremarkable, making this an unlikely diagnosis

Pulmonary embolus causes tachypnea and hypoten-

In this patient:

sion, and OCP use is a known risk factor for thrombo-

• Hypercalcaemia can indeed cause abdominal pain and

embolism. However, Kathyrn has no chest pain,

polyuria but this condition is infrequently seen in a

whereas abdominal pain and vomiting are not usually

young person. Nevertheless, it should be checked out

features of pulmonary embolism

• There is no indication that this patient has chronic

Metabolic acidosis: the respiratory system compen-

renal disease but this should certainly be excluded. The

sates for metabolic acidosis by increasing the respira-

fact that she had three UTIs in 6 months may indicate a

tory rate to blow off CO₂, resulting in respiratory

pathology in the urinary tract. However, urinary infec-

alkalosis, which may fully or partially compensate for

tions are common in female individuals, particularly if

the metabolic acidosis. Causes of metabolic acidosis

they are sexually active

are summarized in Table 27 and DKA is one cause,

• Diabetes insipidus is a recognized cause of polyuria but

which seems to fit the diagnosis. A distinctive ketotic-

is not associated with abdominal pain or vomiting and

smelling breath can further aid the diagnosis of

therefore this diagnosis is unlikely

DKA.

•

Type 1 diabetes mellitus (T1DM) is a strong possibil-

• Abdominal examination revealed only minimal gener-

ity. Diabetic ketoacidosis

(DKA), a complication of

alized tenderness with no signs of acute abdomen (rigid-

T1DM, classically presents with:

ity, guarding or rebound tenderness), which is reassuring

Part 2: Cases

Table 27 Causes of metabolic acidosis.

Metabolic acidosis with increased anion gap

Metabolic acidosis with normal anion gap (imbalance between

(increased acid production/ingestion)

HCO^-3 and H⁺ ions)

Lactic acidosis: increased production of lactate due to

Renal tubular acidosis: loss of HCO−3 or excessive absorption of H⁺

infection, shock or hypoxia

ions

Uraemic acidosis: renal failure

Diarrhoea: loss of HCO3−

Ketotic acidosis: diabetes or alcohol

Pancreatic fistula: loss of HCO3−

Toxins and drugs: salicylate overdose, ethylene glycol and

Addison’s disease: excessive absorption of H⁺ ions

methanol ingestion

Drugs: acetozolamide: excessive absorption of H⁺ ions

and makes a surgical cause for Kathryn’s abdominal pain

attending A&E, and can aid in the diagnosis of anaemia

less likely

(low haemoglobin) and infection (raised white cells). It

is worth bearing in mind that infection may precipitate

What test(s) would you request to

DKA

confirm the diagnosis?

• Cultures: DKA can be precipitated by an infection and,

Taken together, the most likely diagnosis here is DKA,

therefore, blood and urine cultures (as well as culture of

which is characterized by:

sputum if respiratory symptoms are present) are usually

• Metabolic acidosis

requested on presentation, unless the cause of DKA is

• Raised plasma glucose

clear

(non-compliance with insulin injections for

• Dehydration

example)

• Increased ketone production

• Chest X-ray: to rule chest infection as the precipitating

Therefore, the following tests should be requested:

cause. This is perhaps not necessary in newly diagnosed

• Venous bicarbonate and pH: bicarbonate falls in DKA

patients with no reason to suspect a respiratory

to <15 mmol/L and can be as low as 1 mmol/L, resulting

pathology

in a variable degree of acidosis. In early DKA, pH can be

• Electrocardiogram: this should be requested in patients

normal due to compensated respiratory alkalosis. A

with diabetes particularly in the older age group as silent

common hospital practice is to take an arterial blood

myocardial infarction (myocardial infarction with no

sample for bicarbonate and pH measurement (arterial

chest pain) is common in these patients and may precipi-

blood gas analysis), which is unnecessary unless a primary

tate DKA. A myocardial infarction is unlikely here due to

lung pathology precipitating DKA is suspected

Kathryn’s young age but an ECG may show abnormali-

• Plasma glucose: this is elevated in DKA. Capillary

ties and arrhythmias consistent with electrolyte distur-

glucose (finger-prick glucose) can be initially done to

bances (hyperkalaemia for example), which may require

give a quick result but it should always be followed by

urgent attention

plasma glucose measurement

• Abdominal X-ray (AXR): this is usually requested in

• U&Es: in DKA these show:

patients attending A&E with severe abdominal pain and

High or high-normal urea (due to dehydration)

vomiting to rule out intestinal obstruction and/or perfo-

High or high-normal potassium (due to acidosis)

ration. Opinions will differ, but an AXR is probably not

In advanced or more severe cases, creatinine can be

necessary here as Kathryn has no signs to suggest an acute

elevated (due to pre-renal renal failure)

abdomen

• Urine dipstick: detection of large amounts of ketone

bodies in the urine aids the diagnosis of DKA

Blood, urine and radiological tests show the following:

In addition to DKA-specific tests, other blood tests

FBC:

Hb 14.1 g/L

should be requested, including:

WBC 23.3× 10⁹/L (neutrophils 18.2× 10⁹/L)

• Full blood count: usually requested in ill individuals

Platelets 380 × 10⁹/L

Case 1

U&Es:

Na 131 mmol/L

Box 17 Precipitants of DKA

K 5.4 mmol/L

Urea 10.1 mmol/L

• New diagnosis of T1DM in 20% of cases

Creatinine 124 mmol/L

• In a known diabetic patient, DKA can be due to:

Bicarbonate 9 mmol/L

Infection in 35% cases

pH 7.16

Non-compliance with insulin injection in 30%

Glucose

22 mmol/L

Errors in insulin administration and dose calculation in

Amylase normal

15%

CXR

clear

In a minority of patients, DKA may be precipitated by

AXR

normal

an ischaemic event such as myocardial infarction

Urine dipstick: ketones +++, glucose +++, RBC −, WBC −,

nitrates −

How would you manage this patient?

How do you interpret these results?

The management should be directed to:

• Kathryn has high WBC with elevated neutrophil counts

• Correct the metabolic abnormality by replacing:

suggesting an underlying infection. However, DKA

Fluid

patients may have very high WBC count without

Insulin

associated infection, which normalizes once DKA is ade-

Potassium

quately treated. In some cases, infection is difficult to rule

• Treat the precipitating cause (if any)

out, and this is why a septic screen is requested (blood

• Monitor the patient carefully during treatment of

and urine cultures, sputum culture if any, CXR), fol-

DKA

lowed by antibiotic cover if the suspicion of infection

Local hospital guidelines should be followed for the

is high

management of patients with DKA

• The diagnosis of metabolic acidosis is evident from the

combination of low pH and low bicarbonate

Fluid

• The metabolic acidosis together with high plasma

• Fluid replacement usually starts with normal saline

glucose and strongly positive urinary ketones confirm the

(0.9%): 1 L over the first h, 1 L over 2 h then 1 L every

diagnosis of DKA

4-6 h, with careful monitoring of the patient clinical

Patients with DKA excrete large amounts of ketones

status and urine output

in their urine due to deranged glucose metabolism and

• Fluid replacement should be modified according to the

the production of abnormally high levels of ketone

clinical status of the patient. For example, if the patient

bodies: acetone, acetoacetate, β-hydroxybutarate

has a very low blood pressure at presentation with signs

Urine dip testing methods check only for acetone

of shock, initial fluid replacement should be more

and acetoacetate

aggressive

• Other abnormalities include:

• Normal saline should continue until the blood glucose

High urea consistent with dehydration

drops below 12-15 mmol/L (different protocols use dif-

High potassium secondary to acidosis, which shifts

ferent cut-offs), when saline should be substituted with

the potassium from the intracellular compartment to

5% glucose. This helps to restore normal energy metabo-

the extracellular space. Potassium falls with successful

lism and clears the blood of ketone bodies, thereby nor-

treatment of DKA and this should be monitored care-

malizing the pH

fully as detailed below

Marginally low sodium is commonly seen in patients

Potassium

with DKA due to high plasma glucose and this normal-

• Monitoring of potassium status is very important as

izes with treatment of the condition and the fall in

failure to replace potassium can result in severe hypoka-

blood sugar

laemia, which may cause cardiac arrhythmias, potentially

• Urine dipstick is positive for ketones and glucose con-

resulting in death

sistent with the diagnosis of DKA. Of note is the absence

• Serum potassium is usually elevated on initial presen-

of pyuria and nitrates on urine dipstick, making the diag-

tation due to the presence of acidosis, but it quickly drops

nosis of a urinary tract infection unlikely

after the initiation of treatment (both insulin replace-

Part 2: Cases

Table 28 An example of sliding scale insulin. This is only a

• In around one-third, DKA is due to other causes such

guide and different sliding scales can be used as some

as infection or myocardial infarction and these condi-

individuals require higher doses of insulin whereas others need

tions should be treated appropriately

less.

Other measures

Capillary glucose

Insulin dose

• Low-dose heparin to prevent thromboembolism is

recommended by some, but there is no clear evidence to

<4.0 mmol/L

0.5 units/h (with i.v. dextrose): review

support this practice, which is unnecessary unless other

4.1-10.0 mmol/L

2 unit/h

risk factors exist (prolonged immobility)

10.0-16.0 mmol/L

4 units/h

• A nasogastric tube should be inserted into patients

with protracted vomiting

>16.0 mmol/L

6 units/h: review

Monitoring

ment and correction of acidosis shift the potassium from

• Capillary glucose should be checked hourly

the extracellular space into the cells)

• Potassium levels should be regularly assessed and this

• As a rough guide:

can be done using the following time points as a guide:

20 mmol/L potassium should be added to i.v. fluid

presentation (time 0 h), 2 h, 4 h, 8 h, 16 h and 24 h

in patients with normokalaemia

• Both venous bicarbonate and glucose can also be

40 mmol/L to those with hypokalaemia

checked at the same time points as above to assess

No potassium should be given to those with

response to treatment

hyperkalaemia

• The above time points can be modified according to

the severity of the DKA and the response to treatment

Insulin

The management of DKA is summarized in Fig. 37

• Insulin is started as an i.v. infusion at around

(Part 1, p. 57).

0.1 U/kg/h and adjusted according to a sliding scale

insulin (see Table 28)

What is the prognosis in this case?

• Some diabetologists feel that a sliding scale insulin

Prognosis is very good in uncomplicated DKA and the

should be avoided in DKA patients (to avoid too many

mortality rate is less than 3%.

insulin dose adjustments) and the insulin dose should be

regularly reviewed and adjusted by an experienced doctor.

Kathryn improves after initial treatment, her BP normalizes

However, this can be difficult practically and, therefore, a

and her confusion clears. However, she starts feeling very

simple sliding scale is used in most hospitals

weak 12 h after admission and complains of palpitations. An

• A common practice is to give a starting dose of 4-6

ECG is shown (Fig. 39).

units of insulin/h and modify the dose according to

plasma glucose levels

What complication has occurred? How

• Intravenous insulin should only be stopped when the

should this be treated?

urine is ketone-free and the patient is clinically well

• ECG shows changes consistent with hypokalaemia

ST depression

Bicarbonate

Presence of U wave after T wave

• This is very rarely given; only in cases of severe acidosis

• Plasma potassium should be checked and corrected

not responding to conventional treatment

urgently:

• Bicarbonate administration should only be done in an

Supplementation of potassium to i.v. fluid

intensive care setting and after the involvement of senior

A cardiac monitor should be attached to the

clinicians with expertise in DKA management

patient

Precipitating cause(s)

Twenty hours after admission, Kathryn’s blood glucose levels

• Around two-thirds of DKA cases are due to newly

fall to 6.8 mmol/L and the acidosis clears. However, Kathryn

diagnosed type 1 diabetes or compliance problems/errors

becomes suddenly confused and agitated and subsequently

in insulin administration in known diabetic patients

GCS drops to 6.

Case 1

aVR

PRTU

aVL

III

aVF

Figure 39

What urgent test would you request at

acting and three short acting insulin with meals) or

this stage?

two daily injections with a mixture of short and long

• A drop of GCS and neurological signs in a treated DKA

acting insulin preparations. An insulin pump can be

patient should raise the suspicion of cerebral oedema,

used for those with erratic glucose control

which may be secondary to over-enthusiastic fluid

Good diabetes control is important to avoid long-

replacement

term microvascular complications

(retinopathy,

• This complication is rarely seen in adults but it is not

nephropathy and neuropathy) as well as macrovascu-

uncommon in children

lar complications (coronary artery disease, cerebrovas-

• If cerebral oedema is suspected, urgent CT/MRI of the

cular and peripheral vascular disease)

head should be requested, and if the diagnosis is

Tight glucose control should not be achieved at the

confirmed:

expense of increasing hypoglycaemia, which can be

The patient should be immediately transferred to an

dangerous and sometimes fatal

intensive care unit

• Screen for the development of microvascular

Should be treated with mannitol and dexametha-

complications

sone, which may help to reduce the cerebral oedema

Yearly retinal screening

Unfortunately, prognosis is poor once this compli-

Yearly check of urinary microalbumin: usually done

cation occurs, with mortality approaching

90% in

on an early morning urine sample with results

adults

expressed as albumin/creatinine ratio (ACR)

Yearly foot examination to rule out neuropathy:

What does long-term management of a

usually done using monofilament test

type 1 diabetes patient involve?

• Watch for/prevent the development of macrovascular

• Ensure strict glucose control

complications

Monitored by home sugar readings and glycosylated

Have a role threshold for investigating individuals

haemoglobin levels (HbA1c). The input of the diabetes

with suspected vascular pathology

nurse specialist is important to provide support

Add statin treatment to patients above the age of 40

to patients and help with adjustments of insulin

or earlier in those at high risk

doses

Adding aspirin treatment to high-risk individuals is

Most commonly used insulin injection regimes in

of debatable benefit

type 1 diabetes include four daily injections (one long

Aggressively treat hypertension

CASE REVIEW

Kathryn is a young woman admitted to hospital with short

examination usually help to rule out a surgical cause,

history of abdominal pain, vomiting and feeling unwell.

which should be diagnosed early as delays can have serious

Also, there is a history of significant weight loss over a 3-

consequences. There is nothing in the history or

week period. The differential diagnosis of abdominal pain

examination to suggest an acute abdomen, and, therefore,

is wide and a detailed history together with a full

a surgical cause for this patient’s symptoms is less likely.

Continued

Part 2: Cases

Kathryn’s clinical condition subsequently deteriorates and

and inadequate monitoring of her potassium levels, which

her Glasgow Coma Scale (GCS) drops from 15/15 to 13/15.

can fall very rapidly during DKA treatment. She is treated

She is found to be clinically dehydrated, tachycardic

with intravenous fluid containing potassium, which

and tachypneic. Taken together, diabetic ketoacidosis is

stabilizes her condition, but she deteriorates again 24 h

suspected, which is subsequently confirmed by

after admission and her GCS drops to 6. This raises the

demonstrating low plasma pH and bicarbonate levels,

possibility of cerebral oedema and an urgent CT or MRI

raised glucose and significant ketonuria. Appropriate tests

of the head should be requested. If confirmed this

are arranged to rule out an underlying infection (CXR,

complication should be aggressively treated in intensive

blood cultures) and she is treated with intravenous fluid

care settings.

and insulin with initial improvement in her symptoms.

DKA is a common condition and frequently the first

However, 12 h after her admission, she starts complaining

presentation of diabetes. Monitoring is a vital part in the

of palpitations; an ECG shows an abnormal U wave and

management, in order to avoid the development of serious

a depressed ST segment. This was due to hypokalaemia

complications, which may have tragic consequences.

KEY POINTS

• Diabetic ketoacidosis (DKA) is a relatively common

• Treatments for DKA include:

condition, which can be life-threatening

Intravenous fluid (with adequate potassium

• Abdominal pain, vomiting and tachypnea (air hunger) are

replacement)

typical manifestations of this diabetic complication

Intravenous insulin

• DKA should be suspected in any type 1 diabetes patient

Treat the precipitating cause

with gastrointestinal symptoms. In those with no history

Monitoring of glucose, bicarbonate and potassium is

of diabetes, DKA should be suspected in individuals,

paramount to assess response to treatment

particularly the young, who are acutely unwell and have

Intravenous fluid and insulin should be continued until

the above symptoms

bicarbonate normalizes and the urine is ketone-free

• Around one-third of patients with DKA present as a new

• Serious complications of DKA include:

diagnosis of diabetes, one-third are due to errors or

Hypokalaemia (common)

non-compliance with insulin administration in a known

Cerebral oedema (rare)

diabetes patient, and in the final third the DKA arises

• Long-term management of type 1 diabetes patients

secondary to infections or an ischaemic event

should include:

• A history of osmotic symptoms, with or without weight

Good glucose control

loss, should prompt appropriate investigations to rule out

Screen for the development of complications: for

diabetes as a cause

microvascular disease use retinal screening, urinary

• Biochemical abnormalities in DKA include:

microalbumin and regular foot examination; for

Raised blood glucose

macrovascular disease, promptly investigate potential

Low bicarbonate with or without low pH

vascular pathology, initiate statin treatment for

Low pCO₂ on arterial blood gas analysis (not necessary

individuals at high risk or those above the age of 40

to make the diagnosis)

and aggressively treat hypertension and

Heavy ketonuria

microalbuminuria

Case 2

A 35-year-old woman with palpitation

and irritability

Andrea is a 35-year-old solicitor who presents with a 10-day

How would this information help you

history of constant palpitations, weakness and irritability.

in the diagnosis?

• Heat intolerance, hand tremor, loose bowel motions

What is the differential diagnosis and

and weakness are all classical features of hyperthyroidism

how would you proceed?

(symptoms of hyperthyroidism are summarized in Table

Palpitation is a common complaint and is a perception

8, p. 16), making this diagnosis a real possibility

of ‘increased’ heart action. It can be physiological or

• There is a personal history of atopy and a family history

pathological:

of autoimmune diseases, suggesting a genetic predisposi-

• Physiological: stressful life events can result in palpita-

tion to autoimmunity in Andrea

tion. A classical example is palpitations experienced by

• The family history of ischaemic heart disease is prob-

university students or junior doctors sitting an important

ably irrelevant as it did not occur at a young age and

exam

myocardial infarction is not uncommon in men above

• Pathological: cardiac tachyarrhythmias (fast regular or

the age of 70

irregular heart rate) may be due to:

A primary heart problem: in young patients, tachyar-

How would you proceed here?

rhythmias, such as supraventricular tachycardia, com-

Having taken the history, physical examination is the

monly occur with no significant structural cardiac

next step, with special emphasis on the assessment of

abnormality but may sometimes be secondary to

thyroid status. The signs of hyperthyroidism are sum-

serious cardiac abnormalities. However, these are

marized in Table 8, p. 16.

usually intermittent and do not persist for 10 days as

in this case

On examination, Andrea has sweaty palms with a marked

Non-cardiac palpitations: the commonest cause is

hand tremor. Her pulse is regular at 104 beats/min and her BP

hyperthyroidism and, therefore, it is important to rule

is 110/70 with no postural drop. She has a marked lid lag.

this out in our patient

A detailed history and examination is required at this

How would you interpret these findings,

stage.

and what other examination(s) would

you do and why?

On further questioning Andrea tells you that she has had a

Andrea has clinical hyperthyroidism supported by the

number of symptoms for the past week, including: heat

presence of: hand tremor, sweaty palms, tachycardia and

intolerance, hand tremor, generalized weakness, inability to

lid lag. The next step would be directed at establishing

sleep and frequent bowel motions. Her past medical history

the aetiology. Hyperthyroidism is due to Graves’ disease

includes eczema localized to her hands, which is

(GD) in 80% of cases, and, therefore, it is important to

longstanding. Family history includes ischaemic heart disease

look for specific signs of GD, including:

in her father, diagnosed after a myocardial infarction at the

• Smooth symmetrical thyroid goitre

age of 72, her mother suffers from vitiligo and her sister has

• Graves’ ophthalmopathy (GO)

type 1 diabetes.

• Pretibial myxoedema

Andrea has eye signs similar to the patient shown in

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

Fig. 40 (colour plate section). What abnormality do you

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

see? How would that help in the diagnosis?

Part 2: Cases

• The patient has proptosis, marked periorbital oedema

What other tests can be requested in

and conjunctival injection, indicating the presence

patients with hyperthyroidism?

Graves’ ophthalmopathy

• Thyroid peroxidase antibodies are positive in up to

• This is pathognomic for GD and is clinically evident in

80% of GD patients

around 50% of patients with the disease

• Thyroid stimulating hormone receptor (TSHR) anti-

bodies are positive in around 99% of patients if sensitive

methods are used. However, these are not routinely

How would you clinically assess the

requested and are reserved for difficult cases and for

severity of the eye condition? What

pregnant patients

associated condition would you look

for?

What is the treatment of Graves’

The following signs are indications for urgent ophthal-

disease?

mology review:

There are three treatment options for patients with

• Failure of full eye closure

Graves’ disease: medical treatment, radioactive iodine

• Significant ophthalmoplegia

and surgery.

• Evidence of optic nerve compression

The presence of a skin condition called pretibial myxo-

Medical treatment

edema in a patient with hyperthyroidism is also diagnos-

This is used to:

tic of GD but this is found in less than 10% of GD

• Control thyroid function

patients and is almost always associated with clinically

• Induce remission

detectable GO.

The most commonly used antithyroid drugs are

carbimazole and propylthiouracil. These can be given

What would you like to do next?

as:

A neck examination; this usually reveals a smooth and

• A ‘block and replace regime’: a high dose of the drug

symmetrical goitre in patients with GD.

is used and once the hyperthyroidism is brought under

control, L-thyroxine

(T4) is added to avoid

hypothyroidism

What blood tests would you request?

• Titration regime: once euthyroidism is achieved by

This patient should have her thyroid function (TFTs)

high-dose antithyroid drug, a low maintenance dose is

checked.

given to keep the patient euthyroid

Her TFTs show the following (normal ranges):

In the block and replace regime, treatment continues

• Free T4 24.2 pmol/L (10.0-25.0)

for 6-12 months, whereas 18 months is usually required

• TSH <0.05 mIU/L (0.2-6.0)

using the titration regime. Once the treatment is stopped,

the chances of disease remission are around 50%.

How do you interpret these results?

What would you do?

• This patient has a normal FT4, suggesting euthy-

!RED FLAG

roidism

An important side effect, albeit rare, of antithyroid drugs

• TSH is suppressed, consistent with hyperthyroidism

is agranulocytosis and all patients are advised to seek

• The most likely explanation for these results is T3 toxi-

IMMEDIATE medical attention if they develop a sore

cosis, where the thyroid produces excess T3 without sig-

throat, mouth ulcers or high temperature to rule out this

nificant increase in T4 production

serious, and potentially, fatal complication of treatment.

• Therefore, T3 levels should be requested

Her free T3 is 17.5 pmol/L (normal range 3.4-7.2).

Radioactive iodine (RAI)

What conclusion would you make?

This is administered orally, usually as a capsule, and it

This patient has hyperthyroidism due to T3 toxicosis

controls hyperthyroidism in the majority of patients. A

secondary to GD

minority of patients need a second, and rarely a third,

Case 2

dose. A large proportion of patients become hypothyroid

Her TFTs show:

with radioactive iodine therapy and will, therefore,

FT4 39 pmol/L

require thyroxine replacement therapy for life. RAI is

TSH <0.05 mIU/L

contraindicated in:

TSHR-antibodies negative

• Children

Andrea is concerned about the possibility of thyrotoxicosis

• Pregnant and lactating women

due to Graves’ disease.

• Patients with urinary incontinence

• Patients who cannot comply with the safety precau-

Do you agree with her? Why? What

tions following RAI treatment

other blood test would you request?

• This treatment is best avoided in patients with moder-

This patient is unlikely to have Graves’ disease, because:

ate to severe active GO, particularly smokers, as RAI

• She has pain and severe tenderness in her neck, which

may worsen the eye condition. In patients with active eye

are not usual features of Graves’ disease

signs in whom RAI treatment cannot be avoided, it is

• She does not seem to have a goitre

advisable to cover with steroids starting just before RAI

• She has no eye signs to suggest Graves’ ophthalmopa-

treatment and continuing with a reducing dosing regime

thy, nor does she have pretibial myxoedema

for around 6 weeks

• Her symptoms followed a recent viral/bacterial

infection

• Her TSHR antibodies are negative (see p. 15)

Surgery

Taken together (recent infection, thyrotoxicosis, severe

This is reserved for the following patients:

neck tenderness), the likely diagnosis is De Quervain’s

• Failed or contraindicated medical therapy

thyroiditis, which usually occurs after upper respiratory

• Unwilling to have RAI or in whom it is

infections, and thyrotoxicosis is due to thyroid destruc-

contraindicated

tion with consequent release of thyroid hormones, and

• Graves’ disease and a suspicious thyroid nodule

not thyroid hormone overproduction by thyroid cells. In

• Graves’ disease and compressive symptoms

thyroiditis, inflammatory markers are raised and, there-

• Patient preference

fore, C-reactive protein (CRP) should be requested.

Early complications of thyroid surgery include:

• Recurrent laryngeal nerve damage

What test would you request to confirm

• Hypocalcaemia

the diagnosis?

• Local haemorrhage

Thyroid uptake scan would confirm the diagnosis. In

• Wound infection

Graves’ disease there is a uniform increased uptake in the

• Thyroid storm in patients who are poorly prepared for

thyroid gland due to over-activity of the thyroid cells,

surgery

whereas in thyroiditis there is absent uptake due to

Late complications include:

thyroid destruction, as shown in Fig. 41.

• Hoarse voice (secondary to recurrent laryngeal nerve

damage)

How would you treat this patient?

• Hypothyroidism

Treatment is supportive:

• Hypocalcaemia

• β-blockers can be given to control the symptoms of

thyrotoxicosis

Three months later, Andrea brings her friend to see you,

• Pain killers and non-steroidal anti-inflammatory

who has had classical symptoms of hyperthyroidism,

agents are given to control the pain

including hand tremor, increased sweating and palpitations,

• Rarely, in severe cases, short courses of oral steroids

for a week. All these symptoms started following a flu-like

may be necessary

illness. On examination, she has signs suggestive of

The inflammation is self-limiting and the thyroid

hyperthyroidism, including a marked tremor and tachycardia,

gland usually recovers with or without a brief period of

but she has no eye signs or skin abnormality. No goitre is

hypothyroidism.

seen on neck inspection; neck palpation is difficult due to

exquisite tenderness in the area of the thyroid gland but no

What are the causes of thyrotoxicosis?

clear goitre is palpated.

The causes of thyrotoxicosis are listed in Table 29.

Part 2: Cases

(a)

(b)

Figure 41 Thyroid uptake scan showing (a) increased uptake in Graves’ disease and (b) decreased uptake in a case of thyroiditis.

Table 29 The aetiology of thyrotoxicosis.

Associated with increased thyroid hormone production

Not associated with increased thyroid hormone production

by thyroid cells

Graves’ disease (80% of cases of thyrotoxicosis)

Thyroiditis (de Quervain’s, postpartum thyroiditis, following

amiodarone treatment)

Toxic nodule or toxic multinodular goitre

TSH-secreting pituitary tumour

Exogenous thyroid hormone use

Trophoblastic tumour secreting human chorionic gonadotrophin

Production of thyroid hormones from ectopic thyroid tissue

(hCG) with TSH-like activity

(Struma ovarii: a teratoma in the ovary producing thyroid

hormones)

Pituitary thyroid hormone resistance (lack of negative feedback

on TSH secretion)

What are the main points in relation to

Box 18 Graves’ disease during pregnancy

long-term treatment of this condition?

• Remission of Graves’ disease is frequently seen in

• Achieve euthyroidism

pregnancy and the dose of antithyroid drugs can be

Medical treatment: a course of 6-18 months of anti-

reduced and often stopped altogether (usually in the

thyroid treatment can be given, which results in remis-

third trimester)

sion of 50% of Graves’ disease patients. Antithyroid

• Propylthiouracil, rather than carbimazole, is used during

drugs do not induce disease remission in hyperthy-

pregnancy, as some reports suggest a link between

roidism due to other causes

carbimazole use in pregnancy and rare congenital

Radioactive iodine treatment is an effective treat-

defects in the newborn, although this is not fully

ment but commonly results in hypothyroidism. RAI

proven

should not be given to patients with active eye disease

Case 2

Surgery is a treatment option, particularly in indi-

• Patients with Graves’ disease should be monitored for

viduals with large goitres or in those who could not

the occurrence of extrathyroidal complications

tolerate medical treatment

Box 19 Treatment of thyroid storm

• A thyroid storm is a rare but life-threatening complication

Multisystem failure (heart, lung, kidney and liver)

of severe hyperthyroidism

• Management

• It can be precipitated by:

Patient should be transferred to intensive care and a

Infection

senior endocrinologist should be involved in the

Surgery

management

Radiographic contrast agents

Treat dehydration, arrhythmias and infection

Withdrawal of antithyroid treatment

Give high-dose propylthiouracil via nasogastric tube

• Clinical manifestations include:

Give β-blockers (preferably propranolol) as an infusion

Confusion

Cover with high-dose steroids

High fever

Potassium iodide may be used, after starting anti-

Signs of severe hyperthyroidism (including

thyroid drugs, to inhibit thyroid hormone release

tachyarrhythmias)

CASE REVIEW

Andrea, who is 35 years old, consults her doctor with a

Treatment of Graves’ disease includes antithyroid drugs,

short history of palpitations, weakness and irritability. On

radioactive iodine and surgery, and these options should

further questioning, it becomes apparent that she has a

be discussed with the patients. A rare, and potentially fatal,

number of symptoms suggestive of hyperthyroidism

side effect of antithyroid drugs is agranulocytosis, and all

including heat intolerance, hand tremor and insomnia. On

patients should be warned of the possibility of this

examination, she is found to have a hand tremor, sweaty

complication.

palms and lid lag further suggesting hyperthyroidism. A

Jill, Andrea’s friend, also has classical symptoms of

raised T3 (requested after finding normal T4 levels) with

thyrotoxicosis with no clear goitre or eye signs but the neck

suppressed TSH confirms hyperthyroidism. A diagnosis of

is tender to palpation. Also, her symptoms started following

Graves’ disease is made, supported by the presence of a

a viral illness, raising the possibility of thyroiditis as a

smooth goitre and eye changes (Graves’ ophthalmopathy

cause. This is further supported by negative thyrotropin

or thyroid-associated ophthalmopathy). In unclear cases,

antibodies and the diagnosis is confirmed by demonstrating

thyrotropin receptor antibodies can be requested, which

the absence of technetium uptake on thyroid scan.

are positive in more than 95% of Graves’ patients, whereas

Treatment of this condition is symptomatic (β-blockers,

thyroid peroxidase antibodies are positive in around 80%.

pain killers and rarely a short course of steroids).

KEY POINTS

• Hyperthyroidism is a common condition, affecting mainly

• The commonest symptoms of hyperthyroidism include:

the female population, and Graves’ disease is the

heat intolerance, hand tremor, palpitations, frequent

underlying aetiology in 80% of cases. Other causes of

bowel motions, irritability and weight loss despite an

hyperthyroidism include toxic nodule or toxic multinodular

increase in appetite. However, some individuals,

goitre and thyroiditis

particularly the elderly, can present with non-specific

• Hyperthyroidism due to Graves’ disease can be associated

symptoms (apathetic hyperthyroidism)

with extrathyroidal complications, including Graves’

• Treatments for hyperthyroidism include:

ophthalmopathy and pretibial myxoedema

Antithyroid drugs: result in remission of hyperthyroidism

Continued

Part 2: Cases

due to Graves’ disease in around half of individuals.

Surgery: reserved for those with personal preference,

Hyperthyroidism due to other causes usually relapses

active eye disease with intolerance to medical

after stopping antithyroid drugs. Antithyroid drugs may

treatment, large disfiguring goitres and fears of

cause agranulocytosis and patients should be warned

malignancy

about the possibility of developing this serious, but

• A prompt referral to an ophthalmology assessment is

fortunately rare, complication

required in patients with GO if they experience:

Radioactive iodine: one dose of radioactive iodine is

Decrease in visual acuity

effective at controlling hyperthyroidism in the majority

Problems with colour vision

of patients, but hypothyroidism and long-term thyroxine

Inability to fully close the eyelids (leaving the sclerae

replacement is a likely complication. This treatment

exposed)

should be avoided in pregnant women, individuals with

Sudden ophthalmoplegia

urinary incontinence, patients with active eye disease

and children (the latter is not an absolute

contraindication)

Case 3

A 61-year-old man with polyuria,

polydipsia, cough and weight loss

John, who is a 61-year-old postman, presents to his GP with

regular, and respiratory rate 22 breaths/min. A 3.5-cm mass

a 6-week history of increasing tiredness, polyuria and

can be felt in the left clavicular fossa. Chest examination

polydipsia. He also noticed weight loss over the past 6

shows dullness to percussion, reduced breath sounds and

months (around 5 kg) and an irritating cough that seems to

vocal fremitus on the left side. Abdominal examination is

have coincided with him stopping smoking around 5 months

unremarkable.

ago. His past medical history includes a partial gastrectomy

for a gastric ulcer 26 years ago, which according to John

Does this help in making the diagnosis?

was related to heavy alcohol intake. He was a heavy smoker

The patient has signs compatible with a left pleural effu-

(40/day) for 38 years, but stopped 5 months ago due to

sion, a common finding in lung malignancy. Also, there

increasing shortness of breath.

is a large mass in the supraclavicular fossa, which may be

due to lymph node metastasis from a primary lung

What is the differential diagnosis at this

cancer.

stage? What is the next step?

John presents with a 6-week history of polyuria and poly-

What tests would you request in

dipsia, the differential diagnosis of which includes:

this patient?

• Electrolyte abnormalities such as hypercalcaemia

• FBC: anaemia is commonly associated with malignant

• Chronic renal disease

conditions. Pancytopenia can be seen with marrow inva-

• Diabetes insipidus

sion by the tumour (advanced metastatic stage)

• Osmotic diuresis due to high plasma glucose levels

• U&Es: the patient is clinically dehydrated and hyper-

(diabetes mellitus)

calcaemia of malignancy can impair renal function. Also,

• The use of drugs such as lithium and demeclocycline

U&Es should be checked in patients with polyuria and

The rest of the medical history includes:

polydipsia

• Recent weight loss

• Calcium: malignancy can be associated with hypercal-

• Cough and increasing breathlessness

caemia and its presence would explain the polyuria and

• A history of previous heavy smoking

polydipsia in this patient

The history of smoking, respiratory symptoms and

• Glucose: this should be checked in any patient with

weight loss, should raise the suspicion of lung malig-

polyuria and polydipsia to rule out the possibility of

nancy. Polyuria and polydipsia may be due to hypercal-

diabetes

caemia, which can be associated with malignancy

• LFTs: abnormal LFTs may indicate liver metastasis in

(hypercalcaemia of malignancy). The next step is full

a patient with suspected malignancy. However, normal

examination, with special emphasis on the respiratory

liver function does not rule out liver metastasis

system.

• CXR: to investigate the abnormal physical findings

On examination, John looks dehydrated, has a temperature

Tests showed:

of 36.6°C, blood pressure of 130/75, pulse 92 beats/min

FBC: Hb 9.8 g/L, WBC 6.7× 10⁹/L, platelets 365× 10⁹/L

U&Es: Na 145 mmol/L, K 3.6 mmol/L, urea 15.1 mmol/L,

creatinine 192 μmol/L

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

Calcium: 2.8 mmol/L, corrected 3.2 mmol/L (normal range

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

2.1-2.6)

Part 2: Cases

What are the causes of hypercalcaemia?

What is the aetiology of hypercalcaemia

of malignancy?

Causes of hypercalcaemia include:

1 Excessive bone resorption

Primary hyperparathyroidism: relatively common

condition, diagnosed by the presence of hyper-

calcaemia with elevated plasma PTH levels

Hypercalcaemia of malignancy without bony metas-

tasis: due to the production PTH-related peptides

(which mimic the action of PTH)

Hypercalcaemia of malignancy with bony metasta-

sis: bone destruction resulting in hypercalcaemia

Hyperthyroidism: a rare cause of

‘mild’ hyper-

calcaemia

Figure 42

2 Excessive gastrointestinal calcium absorption

Milk-alkali syndrome

Vitamin D toxicity

Random glucose: 5.6 mmol/L

Granulomatous disorders such as sarcoidosis

LFTs (normal ranges):

3 Increased renal reabsorption of calcium

ALT 110 U/L (8-40)

Thiazide diuretic use: these are associated with

AP 465 U/L (36-200)

hypocalciuria, which may result in mild hyper-

Bilirubin 34 umol/L (4-18)

calcaemia

Albumin 25 g/L (30-50)

Familial hypocalciuric hypercalcaemia: an autoso-

CXR (see Fig. 42)

mal dominant condition due to a mutation in the

calcium-sensing receptor. Diagnosis is made by dem-

Comment on these results. What other

onstrating low urinary calcium excretion (in primary

blood test would you request?

hyperparathyroidism, urinary calcium excretion is

These results show:

high)

• FBC: mild anaemia, which is commonly seen in malig-

4 Uncertain mechanisms

nant conditions

Addison’s disease

• U&Es: deranged renal function probably related, at

The mechanisms of hypercalcaemia of malignancy

least

in part, to dehydration secondary to

include:

hypercalcaemia

• Tumour secretion of PTH-related peptide (PTHrP)

• Corrected calcium is elevated. It should be noted that

that mimics the action of PTH

calcium levels should always be adjusted according to

• Bony destruction due to metastases to the bone,

albumin levels, as uncorrected calcium may underesti-

consequently releasing the calcium into the blood

mate hypercalcaemia in subjects with low albumin

stream

• Deranged LFTs suggest liver metastasis and this should

be further investigated with appropriate imaging

techniques

How would you treat John’s

• CXR: a left pleural effusion consistent with the clinical

endocrine problem?

findings

• Fluid replacement is the first step in the treatment of

Parathyroid hormone (PTH) plasma levels should be

hypercalcaemia due to any cause, and usually large

requested in any individual with raised plasma calcium

amounts are required (3-6 L of 0.9% saline over the first

to rule out the possibility of primary hyperparathyroid-

24 h)

ism. In hypercalcaemia of malignancy, PTH is undetect-

• Once the patient is volume replete, intravenous

able, whereas in primary hyperparathyroidism PTH is

bisphosphonates can be used, which are very effective at

high or in the high normal range.

correcting clinically significant hypercalcaemia. Pami-

Case 3

dronate is most frequently used at doses of 30-90 mg

• High-dose steroids may be necessary to treat some

diluted in 0.9% saline

resistant cases of hypercalcaemia of malignancy

• Calcitonin can also be used to treat hypercalcaemia,

which is usually reserved for patients not responding to

bisphosphonate

CASE REVIEW

John, a 61-year-old postman, presents with a few weeks’

malignancy is a strong probability and the osmotic

history of tiredness, polyuria and polydipsia. Other

symptoms may be due to hypercalcaemia of malignancy,

complaints include significant weight loss and a cough that

frequently seen with advanced cancers. Blood tests confirm

coincided with him stopping smoking (used to smoke 40/

hypercalcaemia, in addition to abnormal liver function,

day for almost 40 years) around 5 months ago due to

which may be due to metastatic disease. From the endocrine

shortness of breath. The differential diagnosis of polyuria

point of view, John will need to be rehydrated first and

and polydipsia should be kept in mind and an appropriate

then treated with bisphosphonate infusion to control his

history taken. Weight loss and cough in a smoker should

hypercalcaemia. Longer term, appropriate management of

always raise the suspicion of lung malignancy. On

the lung condition should help to correct his hypercalcaemia

examination, John was dehydrated and a mass was palpable

but repeated bisphosphonate and even steroid therapy

in the supraclavicular fossa. Chest auscultation was

may also be required.

consistent with a left pleural effusion. Taken together, lung

KEY POINTS

• Hypercalcaemia is a common condition and should be

Hypocalciuric hypocalcaemia (should be suspected in the

suspected in individuals with:

presence of family history of hypercalcaemia)

Osmotic symptoms (polyuria, polydipsia)

• Treatments for hypercalcaemia include:

Abdominal pain

Treat the cause

Constipation

In severe symptomatic hypercalcaemia (commonly due to

• Causes of hypercalcaemia include:

malignancy), management includes: intravenous

Primary hyperparathyroidism (common) and tertiary

rehydration, intravenous bisphosphonate and sometimes

hyperparathyroidism (renal failure patients, rare)

steroids (the latter can be effective in resistant

Hypercalcaemia of malignancy

hypercalcaemia of malignancy)

Dietary (milk alkali syndrome)

• Complications of long-term untreated hypercalcaemia

Drugs (thiazides)

include renal calculi, nephrocalcinosis and renal failure

Case 4

A 44-year-old woman with

visual problems

Debra, a 44-year-old woman, is seen by her optician for

• Excessive secretion of ACTH (Cushing’s disease):

recent deterioration of her vision. The optician performs a

Weight gain

visual field test, results of which are shown in Fig. 43.

Easy bruising

Proximal muscle weakness

What abnormality can you see?

Mood disturbance

The visual field test shows bilateral hemianopia.

Menstrual irregularities

Low libido and impotence

Where is the lesion?

Recurrent infections

The lesion is at the optic chiasm. The different types of

Symptoms of diabetes

visual field defects are shown in Fig. 44.

• Excessive production of TSH (TSH-oma): symptoms

of hyperthyroidism as detailed in Case 2

What pathology does the above lesion

• Excessive production of FSH or LH: these are rare and

suggest?

usually present in the same manner as a non-functioning

This suggests a pathology in the pituitary gland such as

pituitary adenoma

a pituitary tumour growing outside the pituitary fossa

If none of the above symptoms is present, then we are

and causing compression of the optic chiasm.

probably dealing with a non-functioning adenoma,

which, if large enough, may cause compression of healthy

What questions would you ask?

pituitary tissue resulting in a variable degree of pituitary

A pituitary tumour may be associated with increased

insufficiency. Therefore, symptoms of hormonal defi-

production of a pituitary hormone or may be a non-

ciency should be considered including:

functioning tumour. Large tumours may result in reduced

• Growth hormone deficiency

production of one or multiple hormones due to com-

Tiredness

pressive effects on normal pituitary cells, and may also

Impaired psychological well-being

result in cranial nerve palsies due to invasion of the cav-

• ACTH

ernous sinus. Therefore, the questions to ask would

Symptoms of primary hypoadrenalism, except for

concern the following symptoms:

the lack of pigmentation

• Excessive production of prolactin (prolactinoma):

• TSH

Galactorrhoea (90% of women, 10% of men)

Symptoms of primary hypothyroidism

Menstrual irregularities

• FSH/LH

Low libido and impotence

Menstrual irregularities

• Excessive secretion of growth hormone (acromegaly):

Reduced libido and erectile dysfunction in men

Change in glove or shoe size

Excessive sweating

What signs would you look for during

Arthralgia, headaches

examination of Debra?

Symptoms of diabetes

• Prolactinoma

Galactorrhoea

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

• Acromegaly

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

Coarse facial appearance (prognathism, increased

Case 4

Figure 43 Results of visual field

testing.

Visual field defects

A. Unilateral visual loss

B. Bitemporal hemianopia

C. Homonymous hemianopia

Figure 44 Visual field defect. A. lesion in the optic

nerve causes loss of vision in the corresponding eye.

B. lesion in the optic chiasm results in a bitemporal

D. Upper homonymous

field defect. C,D. lesion distal to the optic chiasm

quadrantanopia

may result in contralateral homonymous hemi- or

quadrantanopia.

dental separation, frontal bossing, oily skin, tongue

Fig. 45 is an MRI of Debra’s brain. It shows a large

enlargement

pituitary tumour causing compression of the optic

Deep voice

chiasm, and, hence, the visual field defect.

Enlargement of hands and feet

Soft tissue swelling

(may result in carpal tunnel

syndrome)

What tests would you request to rule

Organomegaly

out hormonal excess or deficiencies?

Hypertension

Tests for hormonal excess include:

• Cushing’s disease:

• Prolactinoma: plasma prolactin levels

Facial appearance (round and plethoric face, acne

• Acromegaly: glucose tolerance test. Administration of

and hirsutism)

glucose suppresses growth hormone production and

Truncal obesity with thin extremities

failure of this suppression is strongly suggestive of

Thin and fragile skin

acromegaly

Hypertension

• Cushing’s disease: dexamethasone suppression test.

Osteoporosis (may cause vertebral fracture)

Administration of dexamethasone results in suppression

• TSH-secreting tumour

of cortisol production. Failure of suppression indicates

Signs of hyperthyroidism

Cushing’s syndrome, which may be due to Cushing’s

Part 2: Cases

disease, ectopic ACTH production or excessive produc-

Debra has no symptoms or signs of hormonal excess or

tion of cortisol by an adrenal tumour

deficiency.

• TSH-secreting tumour: TFTs. Thyroid hormones will

be elevated and, in contrast to primary hyperthyroidism,

What one endocrine blood test would

TSH will also be elevated

you request that may have important

Tests for pituitary hormone deficiency include:

implications for the clinical

• TFTs (assess thyroid hormone status)

management in this case?

• Glucagon stimulation test or insulin stress test (assess

• It is important to exclude a prolactinoma (raised pro-

growth hormone and pituitary adrenal axis)

lactin levels), which may be clinically silent (except for

Tests for hormonal deficiencies are not required if the

the local effect), particularly in men

patient is scheduled for emergency surgery. The patient

• The management of prolactinomas is usually medical,

will be covered with steroid during the operation and

and, therefore, patients can be spared surgical

tests for hormonal deficiencies will be done routinely

intervention

after the surgical procedure as surgery itself may result in

• However, large non-functioning tumours may cause

damage to normal pituitary tissue, consequently result-

raised prolactin due to stalk compression, but prolactin in

ing in hypopituitarism.

this case is usually less than 6000 mU/L. In contrast, in

large pituitary macroprolactinoma

(the term ‘macro’

defines tumours >1 cm in diameter) prolactin levels are

usually >10 000 mU/L and can even exceed 100 000 mU/L

Provided all her hormonal tests are

normal, what is the diagnosis and best

treatment option?

• The most likely diagnosis here is a large non-function-

ing pituitary adenoma

• The best treatment option is surgical removal (usually

transphenoidal surgery)

One day after the initial assessment, Debra attends A&E with

severe headaches, double vision, dizziness and vomiting.

What does Fig. 46 show and what is the

diagnosis?

• Fig. 46 shows complete right ptosis, abduction of the

right eye with mydriasis (dilated pupil)

Figure 45

• The diagnosis is right third nerve palsy

Figure 46

Case 4

What complication has occurred? How

Therefore, urgent medical treatment with intravenous

would the patient present and what

cortisol is required in patients with suspected pituitary

test would you request?

apoplexy. Low levels of other hormones are less critical

• The most likely diagnosis is pituitary apoplexy (pitu-

short term, and these can be replaced later

itary infarction)

• Neurosurgeons should be informed as these patients

• The patient typically presents with sudden onset head-

are usually treated with early surgical intervention;

ache, vomiting, visual disturbances and cranial nerve

however, some are managed conservatively if there are

palsies

no visual or neurological symptoms

• Diagnosis is based on typical MRI findings, which

should be requested urgently

How and where should patients with

previous pituitary tumours be followed

What urgent medical management does

up?

she need? What other treatment can be

Individuals with pituitary pathology should always be

offered?

followed up in specialized centres to monitor:

• Pituitary apoplexy is usually associated with cessation

• Recurrence of the disease

of pituitary hormone production due to infarction in the

• Check for the development of complete/partial pitu-

pituitary tissue. This results in low ACTH levels, conse-

itary failure

(particularly those who had pituitary

quently leading to inadequate cortisol production by the

radiotherapy)

adrenal gland, which may result in a hypoadrenal crisis.

• Ensure adequate hormonal replacement

CASE REVIEW

Debra, a middle-aged woman, is seen by her optician for

Debra’s endocrine tests are normal suggesting she has a

recent deterioration of her vision. Her visual field testing

non-functioning pituitary adenoma, for which surgical

shows bitemporal hemianopia suggesting a lesion in the

intervention is the best treatment option. Debra suddenly

optic chiasm, possibly secondary to a pituitary pathology.

develops severe headaches and third nerve palsy, associated

An appropriate history focussing on excess or deficient

with dizziness and vomiting. In view of the large pituitary

pituitary hormone production should be taken in any

tumour, pituitary apoplexy

(infarction) is a strong

individual with suspected pituitary tumour. In this case,

possibility, which is a known complication of pituitary

there are no clear indications for pituitary hormone excess

tumours. Neurosurgeons should be informed of the latest

or deficiency and Debra undergoes an MRI scan, which

development, an urgent MRI requested and the patient

shows a large pituitary tumour compressing the optic

should be covered with steroids (due to potential loss of

chiasm. It is important to rule out the possibility of

ACTH-secreting cells).

prolactinoma

(which responds to medical treatment);

KEY POINTS

• Pituitary tumours may be non-functioning or functional

prolactinoma, which is unique amongst the pituitary

secreting one or more of pituitary hormones

tumours as it can be treated medically without the need

• Individuals with bitemporal hemianopia should be

for surgery in the majority of patients

suspected as having a pituitary tumour. On the other

• Following surgery, patients should be checked for pituitary

hand, pituitary tumours may occur without visual field

hormonal deficiencies using appropriate tests

defects if the tumour is not compressing the optic

• Long-term monitoring for pituitary failure is warranted for

chiasm

patients who have had pituitary radiotherapy (for

• Individuals with pituitary tumours should be assessed both

recurrent or incompletely resected pituitary tumours)

clinically and biochemically for pituitary hormone excess.

• All pituitary patients should be followed up long term in

They should also be assessed for pituitary hormone

specialized centres to monitor disease recurrence,

deficiency and possible cranial nerve pathologies

development of pituitary failure and ensure adequate

• The commonest functional pituitary tumour is a

hormone replacement

Case 5

A 20-year-old man with recent

diagnosis of diabetes

Richard, a 20-year-old man, is referred to the diabetes clinic

• Proximal muscle weakness (hence inability to stand

with newly diagnosed diabetes (fasting glucose on two

from a squatting position).

occasions >10 mmol/L). He has had osmotic symptoms

• Complications of the disease:

(polyuria and polydipsia) for at least 6 months and his

Diabetes

weight has recently increased by around 14 kg. Fig. 47a,b

Hypertension

(colour plate section) shows Richard’s face and abdomen.

The clinical features of Cushing’s syndrome are sum-

marized in Table 30.

What do you see?

• The face appears round (moon-like)

What are the aetiologies of Cushing’s

• There is truncal obesity and abdominal striae

syndrome and what tests would you

request here to confirm the diagnosis?

What questions would you like to

Cushing’s syndrome may be due to:

ask Richard? What signs would you

1. Pituitary adenoma secreting excessive ACTH

look for?

(Cushing’s disease)

Questions should be asked to look for evidence of:

2. Ectopic ACTH secretion due to a malignant tumour

• Easy bruising

secreting ACTH

• Muscle weakness

3. Adrenal tumour secreting excessive cortisol

• Mood disturbances

4. Cushing’s syndrome secondary to exogenous steroid

• Low libido and impotence

use (patients treated with steroids for, e.g. respiratory

Signs to look for include:

problems and rheumatoid arthritis)

• Thin skin with easy bruising

Tests to diagnose Cushing’s syndrome include (detailed

• Proximal muscle weakness

in Part 1, p. 31):

• Hypertension

• Midnight cortisol

• Overnight dexamethasone suppression test

Richard is unable to stand from a squatting position, has

• Low-dose dexamethasone suppression test

very thin skin with multiple bruising and is hypertensive at

• 24-h urinary cortisol

160/95 mmHg.

Once a diagnosis of Cushing’s syndrome has been made,

further tests should be done to establish the aetiology.

Does Richard have type 1 or type 2

• A good clinical history can quickly exclude Cushing’s

diabetes? Why?

syndrome secondary to exogenous steroids

Neither. Richard has a secondary form of diabetes as a

• To differentiate between 1, 2 and 3, ACTH should be

complication of Cushing’s syndrome. Richard has classi-

measured which is elevated in 1 and 2, whereas it is

cal features of Cushing’s syndrome including:

undetectable in 3 (excessive cortisol results in suppres-

• Facial appearance (round ‘moon-like’ face)

sion of pituitary ACTH secretion)

• Truncal obesity and abdominal striae

• Differentiating between 1 and 2 can be more difficult:

• Thin skin and easy bruising

A low potassium is suggestive of ectopic ACTH pro-

duction (hypokalaemia is found in 90%), but it is not

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

diagnostic as 10% of Cushing’s disease patients may

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

have hypokalaemia

Case 5

Table 30 Symptoms and signs of Cushing’s syndrome.

• Radiotherapy can be used as a second-line treatment

following:

Symptoms

Signs

Relapsed disease

Unsuccessful surgery

Weight gain

Facial appearance: round face, acne

• Medical treatment is indicated in:

and hirsutism

The perioperative period

Truncal obesity

Central obesity and abdominal striae

Patients in whom surgery is contraindicated

While awaiting radiotherapy to take effect (which

Easy bruising

Thin skin and easy bruising

may take months to years)

Muscle weakness

Proximal muscle weakness

Drugs used include: metyrapone and ketoconazole

Mood disturbances

Hypertension

• Adrenalectomy: this is usually reserved for cases not

(depression, psychosis)

responsive to the above treatment measures

Menstrual irregularities Impaired glucose tolerance or diabetes

What is cyclical Cushing’s?

Low libido and

Fractures due to osteoporosis

A minority of Cushing’s syndrome patients have

impotence

intermittent cortisol secretion, which can make the life of

Recurrent infections

Vascular disease

the investigating endocrinologist very difficult indeed.

The results of the dynamic tests can only be accurately

interpreted when the disease is clinically active, and,

High-dose dexamethasone suppression test: in pitu-

therefore, repeated investigations are required.

itary Cushing’s cortisol levels fall by >50% of basal

values. However, in a minority of ectopic ACTH-

secreting tumours, cortisol can be also suppressed by

more than 50% of basal values

Box 20 Complications of Cushing’s disease

Inferior petrosal sampling may be necessary to

measure levels of ACTH after corticotrophin releasing

• Hypertension

hormone stimulation in the inferior petrosal sinus.

• Impaired glucose tolerance/diabetes

High central

(in the petrosal sinus) to peripheral

• Osteoporosis

(peripheral vein) ACTH levels are diagnostic of Cush-

• Susceptibility to infection

ing’s disease

• Easy bruising due to thin and fragile skin

If a diagnosis of ectopic ACTH is made, investigations

Other complications vary according to the aetiology of

should focus on finding the tumour secreting excessive

the disease. For example, patients with Cushing’s disease

ACTH.

may have complications related to the pituitary mass

(visual field defect, pituitary apoplexy). Patients with

ectopic ACTH secretion may develop complications

What are the treatment options for

secondary to the presence of a malignant tumour (e.g.

Cushing’s disease?

haemoptysis from a primary lung tumour or complications

• Transphenoidal surgery is the best treatment but is not

arising secondary to metastasis).

always successful

CASE REVIEW

Richard is a young man who presents with new diagnosis

bruising, hypertension and proximal muscle weakness.

of diabetes and significant weight gain. He has evidence of

Cushing’s syndrome can be due to increased ACTH

excessive steroid hormone production

(Cushing’s

production by a pituitary tumour or by non-pituitary

syndrome) manifested as a round and ‘moon-like’ face,

malignant tissue (ectopic ACTH secretion), both of which

central obesity with abdominal striae, thin skin, easy

are associated with increased plasma ACTH levels. In

Continued

Part 2: Cases

contrast, Cushing’s syndrome due to an adrenal adenoma

syndrome can be difficult and requires specialist input.

or exogenous steroid administration are associated with

Complications of Cushing’s syndrome include hyper-

suppression of ACTH production.

tension, diabetes, increased susceptibility to infections and

Tests to diagnose Cushing’s syndrome include midnight

osteoporosis. Treatment of Cushing’s syndrome depends

cortisol, overnight dexamethasone suppression test, low-

on the aetiology of the condition and medical therapy with

dose dexamethasone suppression test and 24-h urinary

metyrapone or ketoconazole can be considered until

cortisol. Differentiation between causes of Cushing’s

definitive treatment measures are used.

KEY POINTS

• Cushing’s syndrome is a condition that arises secondary to

Proximal muscle weakness

increased plasma cortisol levels

Hypertension and vascular disease

• Cushing’s syndrome can be:

Diabetes

ACTH-dependent, e.g. pituitary tumours and ectopic

Increased susceptibility to infections

ACTH production by malignant tissue

Fractures due to osteoporosis

Non-ACTH dependent, e.g. adrenal adenoma and

• Biochemical tests for the diagnosis of Cushing’s syndrome

prolonged, high-dose steroid treatment (for asthma,

include:

rheumatoid arthritis, etc.)

Midnight cortisol

• The main clinical features of Cushing’s syndrome include:

Overnight or low-dose dexamethasone suppression test

Round, ‘moon-like’ face

Urinary cortisol (collection over 24 h)

Weight gain, central obesity and abdominal striae

• Treatment of Cushing’s syndrome differs according to the

Thin skin and easy bruising

aetiology of the condition

Case 6

Tiredness and weight gain in a

30-year-old woman with diabetes

Iwona is a 30-year-old woman with known type 1 diabetes

How does this information help you?

for 12 years. She visits her GP complaining of tiredness and

• The above suggests that Iwona has an organic cause for

weight gain. Her HbA1c levels over the past 7 years have

her tiredness that is probably not directly related to her

ranged between 6.4 and 7.1%, but her most recent test

diabetes

showed an HbA1c of 8.3%.

• Her symptoms should be further explored keeping in

mind the association of type 1 diabetes with other endo-

What would you do at this stage?

crine autoimmune conditions such as hypothyroidism

This is a young woman with type 1 diabetes that has been

and hypoadrenalism

well controlled indicating that she is a reliable and a

• Hypothyroidism is a common disease, particularly in

compliant patient. Her diabetes control has deteriorated

type 1 diabetes and questions regarding specific symp-

recently, which may be related to:

toms of hypothyroidism (Table 9, p. 18) should be asked

• Weight gain

at this stage

• Change in the dose of insulin

• The possibility of hypoadrenalism (Addison’s disease)

• Compliance issues

is less likely as this is usually associated with weight loss

• Problems with

the

injection

sites

(i.e.

and hypoglycaemia (or reduced insulin requirements),

lipohypertrophy)

which are not seen here

• Weight gain may be due to:

Change in lifestyle (different diet, less exercise)

On further questioning, Iwona tells you that her skin is

Endocrine problems

(Cushing’s syndrome,

getting very dry, is feeling constantly cold and her hair is

hypothyroidism)

becoming coarse and brittle. Also, she has had recent

Depression (some individuals with depression tend

problems with menstrual irregularities and has been

to eat more)

constipated.

• Tiredness is a non-specific symptom (reviewed else-

where). In this particular patient, it may simply be due

What would you do now?

to deterioration in diabetes control

Iwona’s symptoms are consistent with hypothyroidism,

A more detailed history at this stage is essential, in

and, therefore, examination of her thyroid status should

particular addressing any change in diet, lifestyle or dose

be the next step (Part 1, p. 34).

of insulin.

On examination, Iwona indeed has dry skin and inspection

Iwona tells you that her diet has not changed but she is

of her face reveals periorbital puffiness. Her pulse is slow at

undertaking less exercise due to extreme fatigue. The dose

52 beats/min regular and she has slow relaxing reflexes.

of her insulin has not changed and she continues in her

Neck palpation reveals no goitre.

current job as a teacher and has no family problems or

social issues of note.

What is your diagnosis so far and what

tests would you request?

• Iwona has classical signs of hypothyroidism (summa-

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

rized in Table 9, p. 18). Therefore, the likely diagnosis is

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

autoimmune hypothyroidism (AH), which may occur:

Part 2: Cases

In the presence of a thyroid goitre, a goitrous form

What do these results indicate?

or Hashimoto’s thyroiditis

• The patient seems to be well replaced with thyroxine

In the absence of a thyroid goitre, the atrophic form

as both her FT4 and TSH are in the normal range

or primary myxoedema

• It is advisable to have the TSH between

0.2 and

• The diagnosis can be confirmed by checking thyroid

2.0 mU/L in patients having thyroxine replacement

function tests

(TFTs) and thyroid peroxidase (TPO)

therapy, which is the case in this patient

antibodies

TFTs are expected to show low thyroid hormones

Iwona comes to see you 2 years later complaining of

and raised TSH

tiredness, muscle cramps, aches and weight gain.

TPO antibodies are usually positive in patients with

What would you do?

Iwona’s TFTs should be checked as her symptoms are

Iwona’s tests show a FT4 of 6.1 mmol/L and TSH of

consistent with under-replacement with thyroxine.

81 mIU/L with positive TPO antibodies.

Her TFTs showed:

How would you manage this patient

FT4

22.1 pmol/L

now?

TSH

15.8 mU/L

• These tests are consistent with AH and the patient will

need T4 replacement therapy

How do you explain these findings?

• Thyroxine treatment can be started in a young patient

• This is a relatively common finding in patients on

at a full replacement dose. In the older age group, in

thyroxine replacement and is usually indicative of

those with cardiac problems, and in longstanding hypo-

non-compliance

thyroidism, an initial small dose is advised with gradual

• The patient is not taking thyroxine regularly causing

titration to an appropriate maintenance dose

an elevation of TSH. However, the patient takes the thy-

• TSH should be rechecked around 6 weeks after starting

roxine before the blood test resulting in normal FT4 but

treatment or after modifying the dose of T4

TSH remains high

• The maintenance dose of T4 is around 1.4 mcg/kg

It takes TSH a few weeks to normalize in patients

having thyroxine replacement and this is why TFTs

Iwona tells you that she is planning a pregnancy in the next

should not be repeated less than 4-6 weeks following

year or so.

initiation or change in treatment

What advice would you give her?

Iwona admits to having some difficulties at work resulting in

• Pregnant hypothyroid women usually need a 30-50%

non-compliance. These issues are subsequently resolved and

increase of T4 dose and this should be fully explained to

her TFTs normalize 3 months later.

patients with hypothyroidism of child-bearing age

She comes to see you again with a skin condition, as

• Iwona should inform her endocrinologist once she

shown in Fig. 48 (colour plate section).

becomes pregnant, in order to increase the dose of T4

and make appropriate arrangements to monitor TFTs

What is the diagnosis?

during pregnancy

• Iwona’s skin shows areas of decreased pigmentation

• The diagnosis is vitiligo

Iwona’s symptoms completely disappear on 100 mcg of T4,

which is further increased to 150 mcg when she becomes

Is Iwona’s skin condition related to her

pregnant 9 months later. She goes through an uneventful

thyroid disease?

pregnancy and the dose of T4 is decreased after delivery to

• Vitiligo is an autoimmune condition that can be asso-

100 mcg/day. Twelve months after delivery her TFTs showed

ciated with autoimmune disorders, particularly autoim-

a FT4 of 18.6 pmol/L and TSH 1.2 mU/L on 100 mcg T4.

mune thyroid disease

Case 6

Box 21 Causes of hypothyroidism

• Autoimmune thyroid disease

• Congenital development and hereditary biosynthetic

Non-goitrous: atrophic hypothyroidism

defects

Goitrous: Hashimoto’s thyroiditis

• Iodine deficiency

• Thyroiditis (including postpartum thyroiditis):

• Thyroid surgery

hypothyroidism is usually preceded by a brief period of

• Secondary (lesion in the pituitary gland or hypothalamus)

hyperthyroidism. It is a self-limiting disease and thyroid

• Thyroid hormone resistance (peripheral tissue fails to

function usually normalizes, with or without a brief period

respond to thyroxine)

of thyroxine treatment

See Table 9, p. 18 for symptoms and signs of

• Drug-induced: amiodarone, lithium

hypothyroidism.

• Post radiation or following treatment with radioactive

iodine

CASE REVIEW

Iwona is a young woman with known type 1 diabetes. She

treated with thyroid hormone replacement. Subsequently,

presents to her GP with classical symptoms of

she becomes pregnant necessitating an increase in the dose

hypothyroidism including tiredness, weight gain, dry skin,

of thyroxine, due to increased requirement of this hormone

cold intolerance, brittle hair and menstrual irregularities,

during pregnancy. Two years after giving birth, her blood

in addition to deterioration in her glucose control. A

test shows raised TSH with normal FT4, which turns out

diagnosis of autoimmune hypothyroidism is made by

to be secondary to non-compliance, the commonest cause

demonstrating low plasma FT4 with increased TSH and

of such a blood abnormality in patients having thyroxine

positive TPO antibodies. Her condition is successfully

replacement.

KEY POINTS

• Hypothyroidism is a common condition, particularly in the

Bradycardia

presence of personal or family history of autoimmunity,

Slow-relaxing reflexes

and it affects mainly the female population

Biochemical abnormalities in hypothyroidism include a

• The commonest aetiology is related to thyroid

raised TSH with low or low-normal FT4. Thyroid

autoimmunity. Other causes include thyroiditis, medical

peroxidase antibodies are usually positive in

treatment (amiodarone, lithium) and iodine deficiency

hypothyroidism secondary to autoimmunity

• Hypothyroidism can present with a wide range of clinical

Treatment of hypothyroidism is simple and involves

symptoms/signs, the commonest being:

thyroid hormone replacement, usually in the form of L-

Tiredness

thyroxine (T4)

Cold intolerance

Dose of thyroxine usually needs adjustment during

Dry skin, brittle hair and puffy face

pregnancy or after weight gain/loss

Weight gain

Constipation

Case 7

Acute confusion in an 82-year-old with

known type 2 diabetes

Brian, an 82-year-old gentleman with known type 2

• Nutritional deficiencies

diabetes, is brought to A&E with general deterioration and

B₁₂

acute confusion.

Thiamine (particularly in alcoholics)

The first step is to take a proper history to narrow

What differential diagnoses would you

down the differential diagnosis. Questions asked should

consider and what would you do?

include:

Older people commonly present to hospital with acute

• Onset of confusion

and subacute confusional states. The differential diagno-

Acute

sis is wide and includes:

Acute on chronic

• Infection:

• Associated symptoms/previous history

Urinary tract infections

(UTIs), which are very

Urinary symptoms or incontinence (UTI)

common, particularly in women

Cough or shortness of breath (chest infection)

Chest infections

Weakness in arms or legs or slurred speech

Encephalitis and meningitis (rare)

(stroke/TIA)

• Drugs and alcohol

Any falls (even mild head bumps may result in a

Intoxication (opiates, sedatives, anticholinergics)

subdural haematoma, particularly in patients treated

Withdrawal

with warfarin)

• Hypoxia

• History of alcohol abuse

Central (sedatives)

• Detailed drug history

Pulmonary (infection)

• Metabolic

It is not possible to take a history from Brian as he is

Uraemia

confused and agitated. Members of his family tell you that

Liver failure

they saw Brian a week ago when he was absolutely fine.

Hypoglycaemia

They stress that he is usually in good health and does his

Hypercalcaemia

shopping and cooking and has been managing alone for 5

• Vascular

years after the death of his wife. Apart from diabetes and

Stroke

‘mild’ hypertension, both diagnosed 10 years ago, he has

Transient ischaemic attack (TIA)

never had any problems with his health. He drinks

• Intracranial lesion:

occasionally (1-4 units/month). His medications include:

Raised intracranial pressure (due to a brain tumour

Metformin 850 mg b.d.

for example)

Gliclazide 40 mg b.d.

Subdural haematoma

Aspirin 75 mg o.d.

• Epilepsy

Atorvastatin 10 mg o.d.

Temporal lobe epilepsy

Bendrofluazide 2.5 mg o.d.

Post ictal states

Does this help you to rule out any of

differential diagnoses mentioned

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

above? What would you do next?

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

• Although limited, the history from the family estab-

Case 7

lishes that this is an acute confusional state in an elderly

What would you do next?

gentleman who is managing to live alone with no appar-

• The normal heart and abdominal examination make

ent problems

primary pathology in the cardiovascular and gastrointes-

• The list of Brian’s medications does not include any

tinal system unlikely, although do not completely rule it

sedatives or opiates and his alcohol intake is minimal,

out

ruling out drugs/alcohol as a cause of his confusion.

• Although full neurological examination was difficult,

However, he is on gliclazide, which may cause hypogly-

the ‘brief version’ described above indicates that it is

caemia. At this stage, an urgent test of capillary glucose

unlikely a major neurological pathology is causing the

is required

above abnormalities. However, this examination does

not conclusively rule out a neurological condition. For

The nurse performs a set of initial assessments and these

example, a subdural haematoma does not necessarily

reveal:

cause any weakness and may manifest as unexplained

Glasgow Coma Scale (GCS) 13/15 (E3, V5, M5)

confusion

Blood pressure 100/58

• The respiratory examination is consistent with lung

Pulse 110/min regular

consolidation, making a diagnosis of pneumonia a strong

Temperature 37.4°C

possibility

Respiratory rate 30/min

• ABG analysis shows:

O₂ saturation 89%

Hypoxia

Capillary glucose ‘high’

Mild metabolic acidosis

Secondary hypocapnia (trying to correct the meta-

What would you do next?

bolic acidosis)

• The patient is hypotensive and tachycardic with a drop

It is essential to test the urine for ketonuria in any

in GCS

diabetes patient with high blood glucose, particularly in

• He has low-grade temperature

the presence of acidosis, to rule out the possibility of

• His oxygen saturation is low

diabetic ketoacidosis.

• His capillary glucose is ‘high’ indicating blood sugar

probably in excess of 30 mmol/L (most capillary glucose

Brian’s urine dipstick shows:

meters fail to accurately measure very high glucose levels

Glucose +++

and simply refer to these as ‘high’)

Ketones +

As Brian is tachypneic with low oxygen saturation, he

WBC negative

should:

Nitrates negative

• Undergo a full physical examination with special

emphasis on the respiratory system

• His arterial blood gases should be checked

Does Brian have DKA? What other

• He should also be started on oxygen therapy

conclusions can be made from the urine

dipstick results?

On examination, Brian is clinically dehydrated although

• Brian’s urine dipstick results are not compatible with

cardiovascular and abdominal examination are both normal.

DKA due to the absence of heavy ketonuria. Mild keto-

Chest auscultation indicates decreased percussion note on

nuria can be frequently seen, particularly in fasted

the right with increased vocal fremitus and bronchial

individuals

breathing. Neurological examination is difficult as the

• The urine dipstick fails to show white cells or nitrates

patient is uncooperative, but it is noted that he is:

in the urine making a UTI an unlikely diagnosis

confused and agitated, moving all four limbs, his pupils are

normal in size with a normal light reflex and plantars are

down going.

What other tests would you request in

Brian’s arterial blood gas (ABG) analysis showed:

this patient?

PO₂ 7.1 kPa

• FBC: looking for raised white cells

(infection),

PCO₂ 2.3 kPa

anaemia

HCO₃ 16 mmol/L

• Blood cultures: raised temperature, likely chest

pH 7.32

infection

Part 2: Cases

• U&Es: checking kidney function, particularly in view

What is the anion gap? What are the

of the dehydration and acidosis

potential causes of his acidosis?

• Glucose: in view of the history of diabetes and raised

Anion gap = (sodium + potassium)

capillary glucose

- (chloride + bicarbonate)

• CXR: in view of the positive findings on examination

• ECG: all acutely unwell individuals, particularly diabe-

Anion gap = (148 + 4.0) − (111 + 15)

tes patients, should have an ECG done to rule out silent

= 26 (normal 12-20)

myocardial infarction and cardiac arrhythmias

His anion gap is high. Causes of high anion gap meta-

• To complete the confusion screen, the following should

bolic acidosis are outlined in Case 1.

be checked:

LFTs

What is his calculated plasma

Calcium

osmolarity?

B₁₂ plasma levels

Plasma osmolarity can be calculated from the

formula:

What is the diagnosis so far and what

would you do while awaiting the results

2 (sodium + potassium) + urea + glucose

of the above tests?

2 (148 + 4.0) + 30 + 54 = 388 (normal 285-295)

• In complicated cases, it is advisable to make a list of

the abnormalities, which usually helps in organizing

His calculated plasma osmolarity is greatly increased.

further investigations and reaching the correct diagnosis.

The abnormalities in this case thus far:

What does his X-ray show? (Fig. 49)

Acute confusion

The X-ray shows right middle lobe pneumonia.

Signs of dehydration

Signs of chest infection

What test would you request next?

Hyperglycaemia

• Brian has an infection and metabolic acidosis; there-

Hypoxia

fore, lactic acid levels should be requested. Metformin

Metabolic acidosis (mild, partially compensated)

can also cause lactic acidosis particularly in the presence

• Taken together, the most likely diagnosis is pneumonia

of renal failure and this is another reason to check lactate

complicated by hyperglycaemia, dehydration and meta-

levels.

bolic acidosis, resulting in confusion and reduced

GCS.

Brian’s lactic acid levels are 5.8 mmol/L (1.0-2.4).

• The patient should be started on i.v. fluid (0.9% saline)

due to dehydration and low blood pressure, as well as

What are the diagnoses?

broad spectrum i.v. antibiotics (after taking appropriate

• Chest infection associated with hypoxia and

cultures) for his chest infection. Oxygen treatment should

hypotension

continue.

• Hyperosmolar non-ketotic hyperglycaemia resulting

in dehydration and contributing to low blood pressure

Brian’s condition quickly deteriorates and his GCS falls to

• Metabolic acidosis due to:

8/15 (E2, M4, V2). His blood tests show:

Raised lactic acid (secondary to infection, hypoxia

FBC Hb 15.7 g/L

and possibly metformin treatment)

WBC 28.3 (neutrophils 25.2)

¥ 10⁹/L

Deranged renal function may have also contributed

Platelets 293

¥ 10⁹/L

to the metabolic acidosis

U&Es: Na 148 mmol/L

K 4.0 mmol/L

How would you treat Brian?

Cl 111 mmol/L

Brian requires treatment for:

Urea 30.1 mmol/L

• Chest infection

Creatinine 223 μmol/L

• Hyperosmolar non-ketotic hyperglycaemia

Bicarbonate 15 mmol/L

Treatment of the infection and normalization of renal

Glucose 54 mmol/L

function will correct Brian’s metabolic acidosis.

Case 7

Box 23 Treatment of hyperosmolar non-ketotic

hyperglycaemia

Broadly similar to that of DKA, but with some differences:

• Fluid: Fluid replacement should be more gentle in

hyperosmolar hyperglycaemia compared with DKA as

these are older patients and more prone to heart failure

with aggressive fluid replacement. In difficult cases, a

central line should be inserted that should guide

appropriate fluid replacement, to avoid sending the

patient into heart failure

• Insulin: Despite the very high glucose levels in these

patients, insulin requirements in non-ketotic

hyperosmolar hyperglycaemia are modest and, therefore,

Figure 49 Courtesy of the Radiology Department, University

insulin should be given at 0.5-2 units/h to achieve a

of Leeds.

gradual drop in blood sugar (around 5 mmol/L/h)

• Potassium: In uncomplicated hyperosmolar non-ketotic

hyperglycaemia, potassium levels do not drop that

quickly with treatment due to the absence of acidosis.

Box 22 Treatment of chest infection

However, the patient may have acidosis due to other

causes (as in the present case) and potassium should,

• Intravenous administration of broad spectrum antibiotics

therefore, be monitored carefully

• Respiratory support as necessary

• Bicarbonate: This is not needed in uncomplicated

hyperosmolar hyperglycaemia as the patient is not

usually acidotic

• Precipitating cause(s): Infection is the most common

What is the prognosis in this case?

precipitating cause and, therefore, antibiotic cover must

• The prognosis of hyperosmolar non-ketotic hypergly-

be started after appropriate cultures

caemia is unfortunately poor

• Other measures: Due to high osmolarity and

More than a third of patients die, commonly from

dehydration, thrombotic disease is very common in

thromboembolic disease

these patients and, therefore, all should be covered

with prophylactic unfractionated heparin (unless

Brian is treated with i.v. antibiotics, fluid and insulin and

haemorrhage is suspected)

• Monitoring: This should be done regularly with blood

makes a very good recovery, with all his blood parameters

samples taken every 2 h in the first 6-8 h to assess

returning to normal 48 h after admission. However, 60 h

response to treatment

after his admission, he complains of sudden onset shortness

of breath. He denies chest pain.

On examination, blood pressure is 110/65 (145/85 earlier

What is the most likely differential

that day), pulse 104 beats/min regular, O₂ saturation 90%

diagnosis?

(98% earlier in the day) and respiratory rate 32 breaths/min.

The most likely differential diagnosis here is:

Cardiovascular auscultation reveals an additional S3 gallop

• Pulmonary embolism

heart sound. Chest auscultation shows bilateral basal

• Relapsed/partially treated chest infection

crepitations.

• Myocardial infarction

Are these findings compatible with a

What would you do?

pulmonary embolus (PE) and why?

• A physical examination, concentrating on the cardio-

• Although PE is a strong possibility, the clinical findings

vascular and respiratory system

do not fit this diagnosis. In large PE, S3, due to right

• ECG

ventricular dysfunction, may be heard but bilateral basal

• CXR

crepitations are not a feature and these are usually found

• Routine bloods

in left ventricular failure

Part 2: Cases

l I

l aVR

IV1

l II

l aVL

l III

l aVF

Figure 50

Table 31 Main features and management of hyperosmolar non-ketotic hyperglycaemic (HONK)

Age group

Older people with or without a history of diabetes (this could be the first presentation of diabetes)

affected

Glucose

Usually very high (30-80 mmol/L)

Acidosis

Not a feature unless complicated by metabolic acidosis due to other causes (i.e. infection or myocardial infarction)

Serum

Very high (>350 mmol)

osmolarity

Ketonuria

There is an absence of severe ketonuria but mild to moderate ketonuria is common (starvation/vomiting)

Precipitating

Common: suspect an infection or a vascular event

factor

Management Gentle i.v. fluid

Gentle i.v. insulin

Prophylactic heparin is mandatory (unless a bleed is suspected)

Aggressive use of i.v. antibiotics is encouraged

• The most likely diagnosis here is left ventricular dys-

What is the diagnosis? How would you

function resulting in pulmonary oedema

explain the absence of chest pain?

• The diagnosis is acute myocardial infarction causing

Brian’s ECG on admission did not show major abnormalities,

left ventricular dysfunction

his repeat ECG is shown in Fig. 50.

• Silent MI (no chest pain) is common in diabetes

patients, and this should be taken into account when

What does the repeat ECG show?

assessing these individuals

The ECG shows ST elevation in V1-V4 indicating acute

The main features of hyperosmolar non-ketotic hyper-

anterior-septal myocardial infarction.

glycaemia are summarized in Table 31.

CASE REVIEW

Brian is an older gentleman who is brought into hospital

lesion or metabolic/nutritional derangements. An

with general deterioration and acute confusion, a common

appropriate history, taken usually from relatives or friends,

clinical presentation in this age group. The differential

is important to give some clues to the cause of the

diagnosis is wide and includes infection, intoxication with

confusion. Physical examination in this gentleman is con-

drugs or alcohol, hypoxia, vascular event, intracranial

sistent with dehydration and chest infection. Subsequent

Continued

Case 7

tests show biochemical evidence of dehydration with raised

However, 2 days later he complains of sudden onset

glucose, together with hypoxia and lactic acidosis secondary

breathlessness without chest pain, which was due to heart

to chest infection. The diagnosis is hyperosmolar non-

failure secondary to silent myocardial infarction. The latter

ketotic hyperglycaemia precipitated by a chest infection.

is common in patients with diabetes and should be

Brian is treated with intravenous antibiotics, fluid and low-

considered in those with recent history of shortness of

dose insulin, subsequently making a good recovery.

breath.

KEY POINTS

• Hyperosmolar non-ketotic hyperglycaemia (HONK) is a rare

• Acidosis is not a feature of HONK, unless it is due to the

complication of type 2 diabetes and usually affects the

associated condition, and there is no heavy ketonuria

older patient

(mild ketonuria may be present due to starvation)

• HONK carries a poor prognosis as mortality rates can be

• Patients with HONK should be treated with intravenous:

as high as 50%

Fluid (careful not to overload and precipitate heart

• In more than half the cases, HONK occurs in patients who

failure)

are not known to have diabetes

Insulin (only small doses are required)

• HONK is frequently precipitated by an infection or

Antibiotics after appropriate cultures (infection is a

vascular event and patients are severely dehydrated with

common precipitating cause)

impaired kidney function and very high plasma glucose

Prophylactic heparin (vascular thrombosis is a common

levels

cause of death in patients)

Case 8

A 42-year-old man with headaches,

increased sweating and

sexual dysfunction

Adrian, who is 42 years old, is seen by his GP for a 5-month

The patient tells you that his:

history of headaches, increased sweating, tiredness and

Headaches are constant, partially relieved by pain killers,

sexual dysfunction.

generalized but more prominent in the frontal region,

have no clear associated symptoms, and he is not

How would you proceed?

suffering increased stress at work or home

Unfortunately, each of the above symptoms is encoun-

Sweating is constant, can be very severe (he sometimes

tered very frequently and at this stage it is unclear

changes his shirt three times/day), and is nocturnal as well

whether:

as during the day

• Symptoms are caused by the same pathology

Sexual dysfunction, he can achieve partial erection but this is

• Symptoms are the result of a number of independent

insufficient for sexual intercourse, and he has had

pathologies

decreased libido, particularly in the past 3 months

Therefore, more information should be obtained on

Tiredness is severe, particularly in the past 4 weeks, and is

each of the above symptoms.

associated with musculoskeletal aches and pains

• Headache

Adrian says that all the above symptoms started around 5

Duration

months ago.

Frequency

Location

Does the above help in the diagnosis?

Associated symptoms

The constant headache for 5 months rules out causes of

Provoking and relieving factors

acute and of recurrent headaches.

Social circumstances (e.g. increased stress at work,

family problems)

Box 24 Causes of acute and recurrent headaches

• Increased sweating

Increased sweating and hot flushes can be features

• Acute headache

Subarachnoid haemorrhage

of hypogonadism in men

Meningitis and encephalitis

Episodes of increased sweating can occur in endo-

Acute sinusitis (but chronic sinusitis is a possibility)

crine diseases such as phaeochromocytoma, acromeg-

Dental caries

aly and carcinoid syndrome

• Recurrent headaches

May be psychological

Migraine

May be idiopathic

Cluster headache

• Tiredness

Trigeminal neuralgia

A non-specific symptom, the differential diagnosis

Glaucoma

of which is discussed elsewhere (Case 10)

• Sexual dysfunction

Subacute headache due to temporal arteritis is unlikely

This is discussed in detail elsewhere (Case 21)

as this occurs after the age of 50 and is commonly associ-

ated with scalp tenderness. Therefore, the cause of Adri-

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

an’s headache is probably related to one of the following

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

diagnoses:

Case 8

• Tension or psychogenic headache

• The feeling of pins and needles in the hands may be

This is a diagnosis of exclusion

due to carpal tunnel syndrome, which can be associated

• Increased intracranial pressure

with acromegaly secondary to soft tissue swelling and

Usually associated with focal neurological signs

compression of the median nerve

Papilloedema on funduscopy

• Signs to look for include:

• Pituitary tumours

Facial appearance (an old photo of the patient is

These can cause a headache, which is usually related

helpful to look for changes): coarse features with

to tumour size

prominent supraorbital ridges, increased dental sepa-

In acromegaly the headache is independent of

ration, prognathism (protrusion of the lower jaw),

tumour size

enlarged nose, lips and tongue and deep voice

Enlarged hands (spade-like hands)

A full neurological examination and funduscopy are both

Thick, oily skin

normal. Formal visual field testing is normal.

Hypertension

Signs of carpal tunnel syndrome

Goitre and organomegalies

Would you make a diagnosis of tension

headache at this stage?

Figure 51 (and Fig. 5 in colour plate section) shows a picture

• A normal neurological examination and the absence

of Adrian. He has a deep voice, greasy skin and his blood

of papilloedema on funduscopy make the diagnosis of

pressure is 170/95.

raised intracranial pressure less likely

• Normal visual field testing does not rule out a pituitary

adenoma

How does this help you in making

• The above information is not enough to make a diag-

a diagnosis?

nosis of tension headache

• Adrian has prominent supraorbital ridges and coarse

• A more detailed history is required asking specifically

facial features

for symptoms of pituitary hormone excess

• Deep voice, greasy skin and hypertension are classic

features of acromegaly

Adrian’s main symptoms are headache and sweating.

• Therefore, the patient is very likely to have

acromegaly

Which pituitary hormone excess should

What biochemical and what radiological

be ruled out first and what specific

tests would you request to confirm the

questions would you ask?

diagnosis?

Increased sweating and headache are common symptoms

• Oral glucose tolerance test: in a normal person, plasma

of patients with acromegaly. Therefore, the questions to

growth hormone levels are suppressed after an oral

be asked should include:

glucose tolerance (OGT) test. In acromegaly there is a

• Changes in glove or shoe size

failure of growth hormone suppression after OGT

• Changes in facial appearance

• MRI of the pituitary looking for a pituitary tumour

• Arthralgia

• Symptoms of diabetes

Adrian fails to suppress plasma growth hormone after OGT

and his MRI shows a pituitary tumour measuring 1.5 cm,

Adrian tells you that he has been unable to take off his

with no optic nerve compression.

wedding ring recently and he has had generalized pain in

his joints as well as a sensation of pins and needles in his

What is the best treatment option for

hands.

this patient?

• Surgical intervention, usually through a transphenoi-

What signs would you look for?

dal approach, is the preferred treatment

• Inability to take off the wedding ring and joint

• Radiotherapy is reserved for patients who fail surgical

pain are consistent with the suspected diagnosis of

treatment or have contraindication to surgical

acromegaly

treatment

100

Part 2: Cases

What medical treatments are there for

Table 32 Main symptoms, signs and complications of growth

hormone excess and deficiency.

patients with acromegaly?

• Somatostatin analogues (octreotide, lanreotide)

Growth hormone excess

Growth hormone deficiency

• Dopamine agonists (bromocriptine, cabergoline)

• Growth hormone receptor antagonist (pegvisomant)

Symptoms

• Radiotherapy

Fast growth (in children)

Failure of growth (in children)

Headaches (independent of

Tiredness

local tumour effect)

Depression

Increased sweating

Box 25 What are the complications of

Decreased body mass

acromegaly?

Musculoskeletal pains

Change in glove/ring and

• Hypertension

shoe size

• Diabetes or impaired glucose tolerance

• Obstructive sleep apnea

Signs

• Increased risk of colonic polyps and colonic carcinoma;

Facial appearance (see text)

Failure of growth and thin

therefore, routine colonoscopy is recommended

skin in children

Soft tissue and skeletal

• Ischaemic heart disease, cerebrovascular disease and

changes

No specific signs in adults

heart failure

Organomegaly

Visual field defect

Deficiency of other pituitary

Can clinical and biochemical acromegaly

hormones

occur in the absence of a primary

pituitary pathology?

Complications

Yes, very rarely acromegaly may occur secondary to

Hypertension

Short stature in untreated

children

excessive secretion of growth hormone releasing hormone

Diabetes

(GHRH)

Hypoglycaemia (mainly in

Colonic polyps and colonic

• Increased secretion from the hypothalamus

children)

carcinoma

• Ectopic secretion from a tumour (such as carcinoid)

Osteoporosis in adults

can result in acromegaly without a primary pituitary

Obstructive sleep apnoea

pathology but this is rare.

CASE REVIEW

Adrian, a middle-aged man, presents with a few months’

presence of an adenoma, indicating that the patient’s

history of headaches, increased sweating, tiredness and

symptoms are due to a growth hormone secreting pituitary

sexual dysfunction. Further questioning reveals changes in

tumour. Treatment of this condition includes surgery and

hand size and symptoms compatible with carpal tunnel

radiotherapy; medical treatment is only partially effective

syndrome. On examination, Adrian has facial features of

at controlling growth hormone production. Complications

acromegaly together with greasy skin and hypertension.

of acromegaly include hypertension, diabetes, obstructive

His neurological examination is normal and he has no

sleep apnea, increased risk of colonic carcinoma and

visual field defects. An OGT test fails to suppress growth

vascular disease

hormone production and a pituitary MRI confirms the

Case 9

Amenorrhoea in an 18-year-old

Sutapa, who is 18, attends her GP clinic complaining of

stress, or hypothalamic tumours or infiltrative lesions]

amenorrhoea.

or general endocrine (these are usually associated with

menstrual irregularities rather than amenorrhoea

What is the differential diagnosis and

and include thyroid dysfunction and Cushing’s

how would you proceed with this

syndrome)

patient?

A full menstrual history is required in order to narrow

Causes of amenorrhoea can be (Fig. 51):

down the differential diagnosis.

•

Physiological

Pregnancy: occasionally some patients do not con-

Sutapa tells you that her menarche occurred at the age of

sider this as a possibility, and rarely the physician fails

13 and her periods have been regular until 9 months prior

to rule this out initially, ending up requesting compli-

to her presentation, when they became less frequent (every

cated, expensive and unnecessary tests

6-7 weeks) and subsequently stopped altogether more than

Lactation

5 months ago. She had three pregnancy tests (most recent a

Menopause

week ago) and they were all negative.

•

Pathological

Primary amenorrhoea: the failure to reach menarche

How does this information help you and

by the age of 16. This may be due to: structural abnor-

what would you do next?

mality

(such as imperforated hymen, congenital

This history of normal menarche and initial regular

absence of the uterus), genetic disorders

(such as

menses rules out primary causes of amenorrhoea. Preg-

Turner’s syndrome), testicular feminization syndrome

nancy is ruled out by three negative tests.

(the individual is genetically a male, with the XY chro-

At this stage specific questions should be asked tar-

mosome, but phenotypically a female due to tissue

geted at secondary causes of amenorrhoea:

insensitivity to androgens) and causes of secondary

• Ovarian and uterine

amenorrhoea (see below)

Hirsutism, obesity (polycystic ovary syndrome)

Secondary amenorrhoea: the cessation of menstrual

Symptoms of oestrogen deficiency: hot flushes,

periods in women who had previously menstruated.

sweating, mood swings (premature ovarian failure)

Causes can be ovarian [such as polycystic ovary disease,

History of gynaecological procedures or pelvic infec-

see Case 13, or premature ovarian failure occurring

tions (uterine adhesions)

due to chromosomal abnormality (Turner’s syndrome),

• Pituitary

gene mutation in gonadotrophin receptors or autoim-

Symptoms of pituitary failure: growth hormone

mune disease, or iatrogenic premature ovarian failure

deficiency, ACTH deficiency

(hypoadrenalism) and

(chemo- or radiotherapy)], uterine (adhesion in the

TSH deficiency (hypothyroidism)

uterus), pituitary (hypopituitarism or prolactinoma),

Symptoms of prolactin excess: galactorrhoea (breast

hypothalamic [excessive exercise (as in professional

milk production)

athletes), severe weight loss, physical or psychological

• Hypothalamic

History of excessive exercise

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

History of recent stress

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

History of weight loss

102

Case 9

103

Pregnancy

Lactation

Menopause

Physiological

Amenorrhoea

Pathological

Primary

Secondary

Genetic

disorders

Structural

Androgen

abnormalities

insensitivity

Ovary

Uterus

Hypothalamus

Pituitary

Figure 51 Causes of amenorrhoea.

Sutapa denies any change in lifestyle or weight, and she is

Table 33 Presentation of prolactinomas.

not having any major stress in her life. However, she

mentions galactorrhoea that is becoming an embarrassing

Symptoms related to excess

Symptoms related to the

prolactin

mass effect

problem.

Galactorrhoea (90% of women,

Headaches

What signs would you look for?

10% of men)

• Galactorrhoea: this can be confirmed on physical

examination

Menstrual disturbances in the

Visual field defects

• Visual field defects: abnormalities suggest a large pitu-

majority

itary tumour

Reduced libido in both women

Hypopituitarism

• Rule out clinical pituitary insufficiency (see Case 4)

and men

Erectile dysfunction in men

Cranial nerve palsies

Sutapa has normal visual fields and no signs to suggest

(invasion of the cavernous

pituitary failure. Galactorrhoea is confirmed on physical

sinus or pituitary apoplexy)

examination.

What is the most likely diagnosis and

• Diagnosis can be confirmed by measuring plasma pro-

how would you confirm this?

lactin levels

• The most likely diagnosis is a prolactinoma (Table

33)

Plasma prolactin is 14 600 mU/L (normal range <600 mU/L).

104

Part 2: Cases

Does this confirm the diagnosis?

What is the best treatment option?

Yes, this confirms the diagnosis of a prolactinoma. Dif-

• Dopamine agonists (bromocriptine and cabergoline)

ficulties can arise when prolactin levels are less than

do not only reduce plasma prolactin levels but also result

6000 mU/L, which may be due to a prolactinoma but

in shrinkage of prolactinomas

may equally be due to a large pituitary tumour with a

• Surgery is usually the best treatment for most pituitary

“stalk effect”, consequently resulting in raised prolactin

tumours except for prolactinomas, where medical

levels.

treatment is first line and surgery is reserved for non-

responders to dopamine agonists

What is the differential diagnosis of

• Successful treatment is associated with a drop in pro-

raised plasma prolactin?

lactin levels, reduction in tumour size and normalization

• Physiological

of menstrual cycles

Pregnancy

Nipple stimulation

Sexual intercourse

Box 26 Difference between micro- and

macroprolactinomas

Stress (taking a blood sample from some individuals

can be a stressful experience and may result in modest

• Microprolactinomas are tumours measuring ≤1 cm in

elevation of plasma prolactin)

diameter

• Drug treatment, there is an extensive list of drugs that

• Macroprolactinomas are tumours measuring >1 cm in

can result in raised prolactin including:

diameter

Dopamine receptor antagonists (metoclopramide)

Neuroleptics (such as chlorpromazine, haloperidol)

Antidepressants

• Patients started on dopamine agonists should be coun-

Opiates

selled regarding pregnancy

Antiretroviral treatment

• Endocrine causes

Sutapa comes to see you 8 months after starting cabergoline

Hypothyroidism (raised TRH stimulates prolactin

treatment to tell you that she is now pregnant.

secretion)

• Metabolic

What would you do with her treatment?

Renal failure (decreased excretion of prolactin)

• In patients with microprolactinomas, it is usually safe

• Hypothalamic

to stop the treatment as tumour expansion is very rare

Mass compressing the stalk

• In patients with macroadenomas, management

Infiltrative disease

remains controversial and should be individualized. A

• Pituitary

large number of patients continue on dopamine agonists,

Prolactinoma

which, particularly bromocriptine, seem to be safe in

Large pituitary tumour causing stalk compression

pregnancy

• This patient should be referred to an endocrinologist

MRI of the pituitary shows a large pituitary adenoma

with experience in managing pituitary pathologies

measuring 1.8 cm in diameter with no optic nerve

Symptoms and signs of pituitary prolactinoma are

compression.

summarized in Table 33.

CASE REVIEW

Sutapa is a young woman who presents with secondary

raised plasma prolactin levels, an abnormality that can be

amenorrhoea and galactorrhoea. Pregnancy is ruled out as

due to a large number of reasons including physiological

the cause of her amenorrhoea, an important step in

causes, certain medications, endocrine and metabolic

investigating amenorrhoea in order to avoid unnecessary

conditions. Further investigations confirm a pituitary

investigations. Apart from galactorrhoea, her physical

macroadenoma as the cause of her raised prolactin.

examination is unremarkable and she does not have signs

Treatment of prolactinomas is usually medical and surgery

of pituitary hormone deficiency. Subsequent tests confirm

is rarely required.

Case 9

105

KEY POINTS

• Secondary amenorrhoea is a common condition and

Physiological (pregnancy, sexual intercourse, nipple

pregnancy should always be ruled out as a cause before

stimulation, stress)

embarking on expensive investigations

Pituitary tumours (prolactinomas or other tumours with

• Causes of secondary amenorrhoea include abnormalities

stalk compression)

in:

Drugs (metoclopramide, antipsychotics and

Hypothalamus (increased stress)

antidepressants, opiates, HIV treatment)

Pituitary (pituitary tumours in general, prolactinomas in

Metabolic and endocrine (hypothyroidism, polycystic

particular)

ovary syndrome, chronic renal failure)

Ovary (polycystic ovary disease)

• Treatment of hyperprolactinaemia should be directed at

Uterus (uterine adhesions following infections)

the cause. In the case of a pituitary prolactinoma, the

• In addition to menstrual irregularities, raised prolactin may

treatment is usually medical, and not surgical, using

cause galactorrhoea

dopamine agonists (bromocriptine, cabergoline)

• There is an extensive list for the causes of

hyperprolactinaemia, including:

Case 10

A 28-year-old with tiredness and

abnormal thyroid function postpartum

One week after her 28th birthday and 6 weeks after giving

Thyroid status: looking for signs of hypothyroidism

birth, Nicola consults her GP, with a 3-4-week history of

Visual field: pituitary failure may occur in the pres-

extreme tiredness. Her GP checks her TFTs and results show:

ence of a large pituitary adenoma

FT4 5.1 pmol/L (normal range 10.0-25.0 pmol/L)

TSH 2.1 mIU/L (normal range 0.2-6.0 mIU/L)

What investigations would you request?

Investigation of pituitary insufficiency involves (Fig. 52):

What questions would you ask?

• Hormonal tests

Results show a low FT4 with inappropriately “normal”

Basal hormone levels: 9:00 am cortisol, very low

TSH, indicating secondary hypothyroidism. Questions

levels can confirm hypoadrenalism (primary or sec-

should be directed towards symptoms of pituitary

ondary). However, levels in the low-normal range are

failure:

non-diagnostic and dynamic tests are required (see

• Tiredness

(hypothyroidism, hypoadrenalism and

below); prolactin, during the period of breast feeding,

growth hormone deficiency)

prolactin levels are high and low levels early in the

• Gastrointestinal

symptoms,

weight

loss

postpartum period are suggestive of hypopituitarism;

(hypoadrenalism)

sex hormones [oestrogen (in females), testosterone (in

• Dizziness

due to

low

blood

pressure

males), FSH and LH] are usually requested in individ-

(hypoadrenalism)

uals with suspected pituitary failure. However, sex

• Failure of lactation (prolactin deficiency)

hormone levels can be difficult to interpret shortly

after giving birth

Nicola tells you that she managed to breast feed for only a

Dynamic tests: glucagon stimulation test

(GST),

week post delivery. She has had dizziness for at least 3

insulin stress test

(IST), low-dose synacthen test

weeks and has been feeling very weak with reduced

(LDST)

appetite and rapid weight loss.

GST and IST assess cortisol and growth hormone

reserve, whereas LDST determines cortisol reserve only

What signs would you look for?

(Fig. 52)

• Dizziness, weakness, reduced appetite and failure to

• Imaging

lactate are strongly suggestive of pituitary failure

MRI of the pituitary gland

• The following should be assessed in individuals with

suspected pituitary failure:

Nicola’s blood tests show low prolactin with inadequate

Blood pressure: low blood pressure is seen in ACTH

cortisol and growth hormone response to IST.

deficiency but it can be in the normal range in patients

with pituitary failure due to preserved aldosterone pro-

What is your diagnosis?

duction by the adrenal gland (which is mainly con-

• Abnormal IST, low prolactin and low FT4 with normal

trolled by the renin-angiotensin system)

TSH is diagnostic of pituitary failure

• Remember that in early pituitary failure an individual

may only have one or two hormonal deficiencies, and as

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

the condition progresses lack of other hormones becomes

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

evident

106

Case 10

107

MRI

gland secondary to hypotension, resulting in hypopitu-

itarism and is called Sheehan’s syndrome. Fortunately,

improved obstetric care in the developed world has made

Imaging

this a rare complication

• The differential diagnosis for the causes of hypopitu-

Investigations for

itarism include:

suspected pituitary

failure

Tumours affecting the pituitary gland

Radiotherapy of the head

Pituitary apoplexy

Endocrine tests

Infiltrative disease (sarcoidosis, haemachromatosis)

Pituitary infection (abscess of the pituitary gland)

Head trauma

Basal tests

Dynamic tests

How would you manage this patient?

• An MRI of the pituitary should be requested to rule

TFTs

PRL

GST

IST

out other causes of pituitary pathology

• She will need hormonal replacements to cover her

E2, Test

LDST

FSH, LH

multiple hormone deficiencies

Figure 52 Investigations for suspected pituitary failure. E2,

Which hormone should be

oestradiol; FSH, follicle stimulating hormone; GST, glucagon

stimulation test; IST, insulin stress test; LDST, low-dose

replaced first?

synacthen test; LH, luteinizing hormone; MRI, magnetic

• Cortisol should be the first hormone to get replaced.

resonance imaging; PRL, prolactin; Test, testosterone; TFTs,

If thyroxine is given before adequate cortisol replacement

thyroid function tests.

it may precipitate a hypoadrenal crisis. Therefore, in pan-

hypopituitarism, cortisol is replaced first followed 48 h

Nicola tells you that she had a difficult labour and lost large

later by thyroid hormone replacement

amounts of blood.

• Female hormones should be replaced using an ade-

quate combination of oestrogen and progesterone

What is the most likely aetiology of her

• In men with hypopituitarism, testosterone should be

pituitary failure and what is the

replaced

differential diagnosis?

• Certain criteria are needed to replace growth hormone

• Severe blood loss can cause infarction in the pituitary

and this is best left to an expert in this field

CASE REVIEW

Six weeks after giving birth, Nicola seeks medical advice

imaging is essential to rule out a pituitary pathology.

for

3-4 weeks’ history of extreme tiredness. An initial

Severe blood loss during delivery may cause pituitary

blood test shows low FT4 with inappropriately normal

failure through infarction, known as Sheehan’s syndrome,

TSH, indicating a diagnosis of secondary hypothyroidism.

which is a possible diagnosis in this case. In individuals

Specific questioning directed at pituitary hormone

with multiple pituitary hormone deficiency, cortisol should

deficiency strongly suggests pituitary failure manifested as

be replaced first, as early replacement with thyroxine may

inability to breast feed (absence of prolactin) and symptoms

precipitate an adrenal crisis. Cortisol replacement is

consistent with steroid hormone deficiency (absence of

important in any individual with suspected adrenal or

ACTH). Further investigations confirm the deficiency of

pituitary failure, with the treatment started even before

several pituitary hormones and a diagnosis of pituitary

initiating investigations in case the patient is acutely

failure is made. In patients with pituitary failure MRI

unwell.

108

Part 2: Cases

KEY POINTS

• Low thyroid hormones with inappropriately low or normal

Polyuria and polydipsia (ADH deficiency): only occurs if

TSH should raise the suspicion of secondary

the posterior pituitary is involved in the pathological

hypothyroidism

process

• Individuals with secondary hypothyroidism should be

• Individuals with pituitary failure should be investigated for

investigated for other pituitary hormone deficiency using

the aetiology of the condition, including:

static and stimulatory hormonal tests

Pituitary or parapituitary tumours

• Clinical features of hypopituitarism include:

Pituitary infarction

Growth arrest in children and tiredness in adults (GH

Infiltrative disease (histiocytosis, haemachromatosis,

deficiency)

sarcoidosis)

Amenorrhoea in women (FSH and LH deficiency) and

Previous radiotherapy

erectile dysfunction in men (LH deficiency)

Trauma (following head injury)

Weight loss and tiredness (ACTH deficiency)

• Management of pituitary failure requires replacement of

Symptoms of hypothyroidism (TSH deficiency)

the deficient hormone(s) and treatment of the cause

Failure of lactation (prolactin deficiency)

Case 11

A 33-year-old man with polyuria

and polydipsia

Peter, aged 33, is referred by his GP following a 2-month

Lethargy

history of polyuria and polydipsia. The patient says that the

Confusion

problem got worse recently and he can pass up to 6 L of

Depression

urine per day.

• Chronic renal failure

Previous history of renal injury

What is the differential diagnosis at

Anorexia

this stage?

Lethargy

The differential diagnosis of polyuria and polydipsia

Itching

includes:

Anaemia

• Diabetes (type 1 or type 2)

Oedema

• Hypercalcaemia

Hypertension

• Chronic renal failure

• Diabetes insipidus (DI)

• Diabetes insipidus

History of head injury

• Diuretic abuse

Intracranial tumours

• Psychogenic

Chronic inflammatory conditions (tuberculosis, his-

It is important to note that some patients complain of

tiocytosis, sarcoidosis)

polyuria without an actual increase in their urine output

Use of drugs (lithium, demeclocycline)

and urine volumes should be measured over 24 h to

confirm the diagnosis of polyuria in uncertain cases.

What tests would you request at

this stage?

What symptoms and signs would you be

• Plasma glucose

looking for to narrow down the

• Plasma calcium

differential diagnosis?

• U&Es

• Diabetes

• Plasma and urine osmolarities

Skin infections

Blurred vision

Blood tests show:

Overweight (T2DM)

Fasting glucose

5.1 mmol/L

History of weight loss (T1DM)

Corrected calcium

2.35 mmol/L

Tiredness

Sodium

147 mmol/L

• Hypercalcaemia

Potassium

3.9 mmol/L

Anorexia

Urea

5.5 mmol/L

Vomiting

Creatinine

88 mmol/L

Abdominal pain

Plasma osmolarity

300 mOsm/kg

Constipation

Urine osmolarity

155 mOsm/kg

What do these results indicate?

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

The above results rule out the following as the cause of

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

this patient’s symptoms:

109

110

Part 2: Cases

Table 34 Results of water deprivation test.

Time

Plasma osmolarity Urine osmolarity

0 h

300

158

4 h

306

154

5 h (i.m. vasopressin

308

155

given)

8 h

295

835

• Diabetes

• Hypercalcaemia

• Chronic renal failure

The high plasma sodium and increased plasma osmo-

larity with inappropriately low urine osmolarity suggest

a diagnosis of diabetes insipidus.

What test would you request to confirm

Figure 53 (a) Courtesy of the Radiology Department,

the diagnosis?

University of Leeds.

A water deprivation test with desmopressin

administration.

The results of Peter’s water deprivation test are shown

in Table 34.

• Infections

Bacterial (Streptococcus, tuberculosis)

How would you interpret these results?

Viral

• These results confirm DI, as the patient fails to con-

Fungal

centrate his urine despite increasing plasma osmolarity

• Inflammatory bowel disease

• Concentration of urine after vasopressin administra-

Malignancy

tion, together with a fall in plasma osmolarity, is consis-

Sarcoidosis

tent with a diagnosis of cranial DI (lack of ADH)

Drugs

(oral

contraceptives, sulphonamides,

penicillin)

The patient had an X-ray done a week ago (Fig. 53a) due

Taken together, the most likely unifying diagnosis is

to persistent cough. He is also complaining of painful and

sarcoidosis causing DI, secondary to the inflammatory

red skin eruptions on his shins, which he has had for

infiltrate in the posterior pituitary. Another remote pos-

3 days (Fig. 53b, colour plate section).

sibility is tuberculosis.

What abnormality can you see on the

What imaging would you request in

CXR? What is the skin lesion? Can you

this patient?

give a unifying diagnosis?

MRI of the pituitary.

The CXR (Fig. 53a) shows bilateral hilar enlargement.

Hilar lymphadenopathy can be seen in:

What is the treatment of cranial DI?

• Sarcoidosis

• Treat the cause

• Infection (tuberculosis)

• Desmopressin can be given:

• Malignancy (lymphoma)

Orally

The red and painful skin lesions are characteristic of

Intranasally

erythema nodosum, which can be seen in:

Injections

Case 11

111

• Drug treatment (only partially effective) includes:

Box 27 Causes of diabetes insipidus

Thiazide diuretics

Prostaglandin synthase inhibitors such as

These can be divided into:

indomethacin

• Cranial

Familial

Acquired: head injury, pituitary tumours, infiltrative

disease (tuberculosis, sarcoidosis, histiocytosis),

What is the main difference in serum

infections (meningitis or encephalitis), vascular events,

and urine osmolarities comparing DI

idiopathic (no cause found)

with psychogenic polydipsia?

• Nephrogenic

• In both DI and psychogenic polydipsia the urine

Familial

osmolarity is low

Acquired: drugs (lithium, demeclocycline), electrolyte

• Plasma osmolarity is high in DI but low or low-normal

abnormalities (hypokalaemia, hypercalcaemia), chronic

in psychogenic polydipsia

renal disease

• In difficult cases, a water deprivation test should

be performed to differentiate between these two

What is the treatment of

conditions

nephrogenic DI?

Table 35 summarizes the main features of cranial and

• Treat the cause and maintain adequate fluid intake

nephrogenic DI as well as psychogenic polydipsia.

Table 35 Main features of cranial and

Cranial DI

Nephrogenic DI

Psychogenic polydipsia

nephrogenic DI and psychogenic

polydipsia.

Posmo

High-normal or high

Low-normal or low

Uosmo Low

Low

After water deprivation test

Posmo

High

Normal

Uosmo Low

Low

Normal

After desmopressin administration

Posmo

Normal

High

Normal

Uosmo Increase (normalizes)

Low

Normal

Posmo, plasma osmolarity; uosmo, urine osmolarity.

CASE REVIEW

Peter consults his doctor with a

2-month history of

ADH), rather than nephrogenic DI (reduced responsiveness

polyuria and polydipsia. Diuretic abuse, diabetes,

of the kidneys to ADH). The patient has an abnormal CXR

hypercalcaemia and chronic renal failure are ruled out as

with bilateral hilar enlargement and a skin lesion consistent

a cause for his symptoms. Diabetes insipidus is suspected,

with erythema nodosum. This strongly suggests a diagnosis

which is confirmed following a water deprivation test. An

of sarcoidosis as a cause for this patient’s DI. Treatment of

improvement in urine osmolarity after vasopressin

cranial DI is replacement with desmopressin, which can be

injection indicates a diagnosis of cranial DI (deficiency of

given orally, intranasally or subcutaneously.

Case 12

A 62-year-old man with tiredness

and hyponatraemia

Max, a 62-year-old gentleman, is seen by his GP with a few

Max tells you that he started to feel increasingly tired 6

days’ history of severe tiredness. Routine blood tests are

weeks ago, lost his appetite and this was associated with

requested and these show:

weight loss. Past medical history includes temporal lobe

Na+

119 mmol/L

epilepsy for which he has been on treatment for more than

K+

3.4 mmol/L

15 years. On examination he looks well hydrated and his

Urea

4.2 mmol/L

physical examination is unremarkable.

Creatinine

65 μmol/L.

How would the above information help

What differential diagnosis would you

in establishing a diagnosis?

think of at this stage?

• Max is clinically well hydrated

Hyponatraemia is a common finding and not infre-

• The urea is not elevated further suggesting that the

quently mismanaged. A large proportion of patients with

patient is well hydrated

hyponatraemia are initially diagnosed as syndrome of

It should be noted that in malnourished individuals

inappropriate ADH secretion (SIADH) without proper

(such as alcoholics) urea can be very low, and, there-

assessment. Hyponatraemia may be due to (Fig. 54):

fore, urea in the normal range does not rule out

• Sodium loss and dehydration (in which case the patient

dehydration

is hypovolaemic):

• Taken together, hyponatraemia secondary to dehydra-

Use of diuretics (a very common cause)

tion is unlikely here

Diarrhoea

• A normal physical examination further rules out:

Vomiting

Cirrhosis

Renal disease and salt wasting

Cardiac failure

Mineralocorticoid deficiency: hypoaldosteronism or

Nephrotic syndrome

Addison’s disease

Hypothyroidism

(but in some case individuals

• Water excess with euvolaemia:

with hypothyroidism may have very few clinical

SIADH

signs)

Glucocorticoid deficiency

Hypothyroidism

What is the likely diagnosis from the

• Water excess with hypervolaemia:

clinical evidence given above?

Cirrhosis

• The likely diagnosis is SIADH

Cardiac failure

• Glucocorticoid deficiency and hypothyroidism remain

Nephrotic syndrome

two possibilities and these should be ruled out

What would you like to do at

this stage?

What tests would you request to

• A full medical history, including a review of current

confirm the diagnosis?

medications

• Plasma osmolarity

• Clinical examination

• Urine osmolarity with urinary electrolytes

• TFTs (to rule out the possibility of hypothyroidism)

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

• A random cortisol with or without a synacthen test (to

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

rule out glucocorticoid deficiency)

113

114

Part 2: Cases

Renal

skin

Addison’s

Aldosterone

disease

deficiency

Fluid loss

Mineralocorticoid

deficiency

Hypovolaemia

Hyponatraemia

Euvolaemia

Hypervolaemia

Heart

Nephrotic

SIADH

deficiency

Failure

syndrome

Figure 54 Causes of hyponatraemia.

GC, glucocorticoid; SIADH, syndrome

Hypothyroidism

Cirrhosis

of inappropriate antidiuretic hormone

secretion.

Before the blood is taken for the above

A previous U&Es result would help in differentiating

tests, what would you like to know?

hyponatraemia due to drug use

A review of current medications is essential (particularly

the use of diuretics and thyroxine).

Max had his U&Es checked 6 months ago which showed:

Sodium

136 mmol/L

The list of medications includes carbamazepine and

Potassium

4.3 mmol/L

paracetamol as required.

Urea

3.8 mmol/L

Max’s tests showed:

Creatinine

67 μmol/L.

Plasma osmolarity

243 mOsm

Urine osmolarity

487 mOsm

Urine sodium

52 mmol/L

Random cortisol

620 nmol/L

Box 28 Causes of SIADH

FT4

21 pmol/L

TSH

1.8 mIU/L.

• Malignancy

• Chest infections (particularly atypical pneumonia)

What is the diagnosis?

• Abnormalities in the central nervous system

• Max has a normal thyroid function and no evidence of

Infections

glucocorticoid deficiency

Head injuries

• Max has:

Vascular disorders

Low plasma osmolarity

• Metabolic

Inappropriately high urine osmolarity

Porphyria

High urinary sodium excretion

• Drugs

Chemotherapy

The diagnosis is, therefore, SIADH.

Psychiatric drugs

Anti-epileptics (carbamazepine)

What is the aetiology of SIADH in

Antidiabetics (chlorpropamide)

this case?

• Idiopathic

•

A possibility is carbamazepine use

Case 12

115

• If the above tests are negative, whole body CT should

be considered

The patient’s abdominal ultrasound is shown in Fig.

55.

What does this section of the liver

show? What is the likely diagnosis?

The ultrasound shows multiple hepatic metastases, and,

therefore, the likely cause of SIADH is metastatic

malignancy.

Figure 55 Courtesy of the Radiology Department, University of

How would you manage Max’s

Leeds.

hyponatraemia?

• Fluid restriction (750-1500 mL/day)

• Treat the underlying cause if possible

What do these results indicate?

• In long-term cases, demeclocycline can be tried (which

The normal sodium 6 months earlier makes SIADH

induces nephrogenic diabetes insipidus)

secondary to carbamazepine use unlikely.

!RED FLAG

What would you do now?

• Malignancy as a cause of SIADH should be ruled out,

Hyponatraemia should be corrected slowly (0.5 mmol/h

particularly in view of the recent history of weight loss

and less than 10 mmol/24 h) to avoid the rare

• A number of tests can be requested at this stage

complication of central pontine myelinolysis.

including:

In severe hyponatraemia with neurological signs (seizures),

CXR

rapid correction of the low sodium to a ‘safe level’ may

Abdominal ultrasound

be necessary and can be achieved by infusion of

Prostate specific antigen (PSA; rule out cancer of the

hypertonic saline.

prostate)

CASE REVIEW

Max, who is 62 years old, consults his doctor with a history

Max is on long-term treatment with carbamazepine.

of tiredness. Initial investigations show significant

However, his plasma sodium levels 6 months earlier, when

hyponatraemia and he is, therefore, admitted to hospital

he was on the same treatment, were normal casting doubts

for further management. Hyponatraemia can occur in

about this diagnosis. He is subsequently investigated for

the presence of hypovolaemia, euvolaemia or hypervolaemia.

the possibility of malignancy as a cause of his SIADH and

Assessing hydration status of the patient is important

liver ultrasound confirms the presence of multiple

to plan appropriate investigations. Max appears well

metastases. Max is subsequently managed by fluid

hydrated and on further questioning it became apparent

restriction and treatment of the underlying pathology is

that he lost significant weight recently due to poor appetite.

considered. Correction of hyponatraemia should be done

His clinical presentation, plasma and urine osmolarities

gradually, particularly if sodium levels are very low, to

and urinary electrolytes are consistent with SIADH. The

avoid the rare but serious complication of central pontine

possibility of drug-induced SIADH is considered as

myelinolysis.

116

Part 2: Cases

KEY POINTS

• Hyponatraemia is a common condition in hospitalized

With hypervolaemia: cirrhosis, heart failure and renal

patients

failure

• It is very important to assess fluid status in individuals

• Diagnosis of SIADH is confirmed by demonstrating low

with hyponatraemia (hypovolaemic, euvolaemic,

plasma osmolarity in the presence of high urine osmolarity

hypervolaemic) together with a review of their

and high urinary electrolyte concentration

medications (diuretics and inappropriate fluid replacement

• Treatment of SIADH includes:

probably remain the commonest cause of hyponatraemia

Treat the cause

in hospitalized patients)

Fluid restriction

• Causes of hyponatraemia include:

Medical treatment is considered in difficult cases

With hypovolaemia: renal salt loss (diuretics, tubular

• Treatment of other causes of hyponatraemia should be

defect, mineralocorticoid deficiency) and gastrointestinal

directed at the cause

loss (vomiting, diarrhoea)

With euvolaemia: SIADH, glucocorticoid deficiency and

hypothyroidism

Case 13

Excess hair in a 29-year-old woman

Julie is 29 years old and is complaining of excess hair on her

mented hair occurring in areas where men normally

neck, chin and body.

develop hair growth

Androgen-independent hair growth: excess vellus

What differential diagnosis would you

hair over face and trunk

consider at this stage?

Excess hair or hirsutism is a common complaint affecting

What signs would you be looking for?

more than 10% of women.

• Assess severity and distribution of hirsutism (special

Causes include:

tables can be used for this)

• Polycystic ovary syndrome (PCOS): common

• Distinguish between androgen-dependent and

• Familial or racial (for example Mediterranean origin):

androgen-independent hair growth

common

• Look for signs of virilization: these are usually associ-

• Drugs (phenytoin, corticosteroids, cyclosporine, ana-

ated with an androgen-producing tumour

bolic steroids, minoxidil)

• Abdominal examination: looking for abdominal

• Congenital adrenal hyperplasia: rare

masses (ovarian tumour)

• Cushing’s syndrome: rare

• Signs of Cushing’s syndrome

• Ovarian and adrenal tumours: rare

• Acanthosis nigricans: this can be associated with

• Idiopathic

insulin resistance suggesting a diagnosis of PCOS

Julie tells you she always had excess body hair but this

What questions would you ask to try to

started to worsen in the past 18 months or so. Her periods

establish a diagnosis?

have been irregular for the past 8 years occurring every 2-3

• Onset: long history or recent problem; a recent history

months. There is a family history of T2DM but there is no

of hirsutism, particularly in severe disease, warrants

history of hirsutism.

prompt and full investigations

On examination, she is overweight with a BMI of

• Family history of hirsutism (familial hirsutism)

32.4 kg/m². She has a lesion in her axilla, shown in Fig. 56

• Menstrual history: normal periods effectively rule out

(colour plate section). She has excess hair on her chest, chin,

significant hyperandrogenism

(ovarian and adrenal

abdomen and inner thighs (noted as “mild”). There are no

tumours unlikely)

signs of virilization.

• History of virilism

Change of voice

Given the information above, what is

Clitoromegaly

the most likely diagnosis?

Frontal bolding

The most likely diagnosis is PCOS supported by:

Increased muscle mass

• Long history of hirsutism and oligomenorrhoea

• Distinguish between:

• Obesity

Androgen-dependent hair growth: coarse and pig-

• Excessive hair in androgenic distribution

• Absence of signs of virilization

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

• Presence of acanthosis nigricans suggesting increased

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

insulin resistance, which is a feature of PCOS

117

118

Part 2: Cases

Can you rule out an androgen secreting

• Raised LH/FSH ratio

tumour from history and examination?

• Impaired fasting glucose

An androgen secreting tumour in this patient is highly

Taken together, the most likely diagnosis is PCOS. The

unlikely due to:

failure to detect polycystic ovaries on abdominal ultra-

• Slow onset of symptoms

sound does not rule out the diagnosis, particularly as this

• Absence of virilization

has a lower sensitivity compared with transvaginal

ultrasound.

What tests would you request to

What other blood test(s) would

confirm the diagnosis?

you request?

• Testosterone: normal or mildly elevated in PCOS

This patient should undergo a glucose tolerance test due

(<5 nmol/L)

to her impaired fasting glucose.

• SHBG low in more than half of PCOS women, conse-

quently resulting in high free androgens

What are the treatment options

• FSH and LH: high LH/FSH ratio in two-thirds of

for Julie?

PCOS

• Weight loss, this is important as it results in:

• Ovarian ultrasound: typical ovarian morphology can

Reduction in hyperandrogenism

be seen in the majority of PCOS patients (particularly

Increase in insulin sensitivity

using transvaginal ultrasound)

A minor reduction of weight by 5% can result in 50%

• Other tests:

improvement in hirsutism.

Fasting glucose

(diabetes in

10% and impaired

• Oral contraceptive pills (OCP), the most commonly

glucose tolerance in 40% of PCOS patients)

used is Dianette which contains:

Lipids

Oestrogen (ethinyl oestradiol)

Androgen receptor blocker (cyproterone acetate)

Julie’s blood tests show the following (normal ranges):

• Insulin sensitizers

Testosterone 2.8 nmol/L (1-2.5)

Metformin: has been successfully used to restore

SHBG 9 nmol/L (22-120)

ovulation and induce fertility in PCOS

FSH 2.4 U/L

Thiazolidinediones: rosiglitazone and pioglitazone

LH 5.3 U/L

are less frequently used compared with metformin

Fasting glucose 6.8 mmol/L

• Anti-androgen treatment

Triglyceride 2.1 mmol/L

Cyproterone acetate: increases hepatic androgen

Cholesterol 4.8 mmol/L

clearance

Prolactin 445 (<600 mU/L)

Spironolactrone: weak anti-androgen

17-OH progesterone 12 nmol/L (1-20)

Flutamide: strong anti-androgen

Abdominal ultrasound: Normal appearance of the ovaries

• 5α-reductase inhibitors

Finasteride: inhibits the conversion of testosterone

to the potent androgen dihydrotestosterone

Why did Julie have her prolactin and

It should be noted that women with PCOS receiving

17-OH progesterone checked?

pharmacological treatment should be given appropriate

• Prolactin was checked as a routine test investigating

contraceptive advice.

her irregular periods (see Cases 4 & 10)

• 17-OH progesterone was checked to rule out the pos-

Julie is very keen on starting a family.

sibility of congenital adrenal hyperplasia (discussed in

What advice would you give her and

Case 13)

would you start her on any

pharmacological treatment?

What is the diagnosis?

• The importance of weight loss should be emphasized

Julie has:

• Metformin treatment has been shown to restore ovula-

• Mildly elevated testosterone

tion in some patients with PCOS and therapy with this

• Low SHBG (consequently increasing the levels of

agent is a possibility. Other treatment options are sum-

unbound/free testosterone)

marized in Table 19, p. 41.

Case 13

119

CASE REVIEW

Julie is a young woman who presents with hirsutism and

acanthosis nigricans, a condition associated with insulin

menstrual irregularities. More than 10% of women have

resistance, together with excess hair in androgenic

varying degrees of hirsutism, with the commonest causes

distribution with no signs of virilism. The most likely

being polycystic ovary syndrome and familial or racial

diagnosis is polycystic ovary syndrome, which is further

predisposition. It is important to take a full history

supported by biochemical tests showing mildly raised

including onset of symptoms, menstrual history and

testosterone with low SHBG and elevated LH/FSH ratio

markers of virilism. Severity of the condition should be

together with impaired fasting glucose. Treatment for this

assessed and causes of secondary hirsutism should be

condition includes weight reduction, oral contraceptive

looked for. Julie is overweight and is found to have

pills, insulin sensitizers and anti-androgen treatment.

KEY POINTS

• Hirsutism in women is a common complaint

Clinical presentation

• Causes of hirsutism include:

Low sex hormone binding globulin (SHBG) with or

Common: polycystic ovary syndrome (PCOS), and

without mildly elevated testosterone levels

familial or racial

Raised LH/FSH ratio

Rare: adrenal or ovarian tumours, congenital adrenal

Cystic ovaries on ultrasound (transvaginal is more

hyperplasia and Cushing’s syndrome

accurate than transabdominal)

• Rapid onset of symptoms, particularly in the presence of

• Treatment of PCOS includes:

virilization, warrants prompt and full investigations

Weight loss

• The majority of women with hirsutism have PCOS, which

Oral contraceptive pills (result in elevated SHBG and,

is further characterized by:

hence, lower free testosterone)

Menstrual irregularities

Insulin sensitizers (metformin is the most commonly

Obesity

used agent)

Insulin resistance (hyperinsulinaemia with or without

Androgen receptor blockers (cyproterone acetate,

high glucose levels)

spironolactone)

• PCOS is diagnosed by:

5α-reductase inhibitors (finasteride)

Case 14

A 52-year-old woman with paroxysmal

atrial fibrillation and abnormal

thyroid function

Bridget, who is 52 years old with a past medical history of

In the first 3 months of amiodarone use, TSH may

paroxysmal atrial fibrillation, was referred with the following

be elevated (lack of full negative feedback on the pitu-

thyroid function results:

itary due to low T3 levels)

FT4

30.1 pmol/L (10.0-25.0)

After 3 months, the pituitary seems to adjust to the

FT3

4.7 pmol/L (3.4-7.2)

low normal T3 concentrations and TSH normalizes

TSH

3.5 mIU/L (0.2-4.5)

The combination of high FT4, normal T3 and TSH in

TPO antibodies negative

an individual taking amiodarone is not uncommon and

Bridget is asymptomatic.

does not require any medical intervention at this stage,

but will require regular monitoring.

What would you like to ask the patient?

• The patient has unusual TFT results with elevated FT4,

Bridget’s repeat TFTs in 3 months show:

normal T3 without suppression of TSH

FT4

25.1 pmol/L

• Drug history should be established (is the patient on

FT3

4.1 pmol/L

thyroxine or other treatment that may alter thyroid

TSH

3.8 mIU/L

function?)

What would you do now?

Bridget denies ever taking any thyroxine. Her medication

• Nothing

includes: amiodarone (started 3 months ago), warfarin,

• Keep monitoring TFTs every 3-6 months

ibuprofen and paracetamol

Bridget is referred 18 months later by her GP with clear

Can you explain her abnormal

symptoms and signs of hyperthyroidism and TFTs showing:

TFTs now?

FT4

67 pmol/L

• Amiodarone use can impair thyroid function in a

FT3

19.1 pmol/L

number of ways

TSH

<0.05 mIU/L

It can result in abnormal TFTs, which have no clini-

cal significance

What do these results indicate?

It may cause clinical hyperthyroidism

Bridget now has frank primary hyperthyroidism as shown

It may result in clinical hypothyroidism

by:

• Due to suppression of T4 to T3 conversion, amioda-

• High thyroid hormones (both T3 and T4)

rone use can be associated with:

• Suppressed TSH

High FT4 concentrations, without clinical hyperthy-

Bridget has amiodarone-induced hyperthyroidism.

roidism (therefore, it is essential to check T3 in patients

receiving amiodarone treatment)

What other tests would you request?

Low FT3 concentrations

(usually low normal

• Thyroid autoantibodies

levels)

• CRP

• Thyroid ultrasound (Doppler studies)

In type 1 AIT:

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

Thyroid antibodies are positive in the majority

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

CRP levels are usually normal

120

Case 14

121

Table 36 Differentiation between type 1 and type 2

How would you treat the patient?

amiodarone-induced thyrotoxicosis (AIT).

The patient’s investigations are consistent with type 2

AIT and the treatment includes:

Type 1 AIT

Type 2 AIT

• Discontinuation of amiodarone if possible

• High-dose oral steroids (prednisone 40 mg daily.)

Clinical

Goitre

Usually present

Absent

The cardiologists are keen to continue amiodarone

treatment and Bridget is started on steroids for 4 weeks

Blood tests

followed by a reducing dose. Her TFTs 3 months later (off

Thyroid autoantibodies

Positive (majority)

Negative

steroids) showed:

Plasma CRP

Normal

Elevated

FT4

21.1 pmol/L

FT3

4.6 pmol/L

Doppler studies and RAI uptake

TSH

3.9 mIU/L.

Vascularity

Increased

Decreased

Radioiodine uptake

Normal or reduced

Absent

What do these results indicate?

The patient is now euthyroid and no action is required

Treatment

other than regular monitoring of her TFTs.

Antithyroid drugs

Yes

Steroids

Yes

Bridget is seen 3 months later with the following TFTs:

FT4

12.1 pmol/L

FT3

3.8 pmol/L

TSH

10.1 mIU/L

Box 29 Amiodarone-induced hyperthyroidism

She is clinically asymptomatic.

• Type 1 amiodarone-induced thyrotoxicosis (AIT): similar

to autoimmune hyperthyroidism (increased production

What would you do?

of thyroid hormones)

• The blood tests are consistent with subclinical

• Type 2 AIT: similar to thyroiditis (thyroid destruction and

hypothyroidism

release of thyroid hormones)

• The patient is likely to become clinically hypothyroid

It is important to differentiate between the two types as

(which is not uncommon after type 2 AIT, due to thyroid

they are treated differently (see Table 36). Some patients

may have a mixed type, in which case they should be

destruction)

treated for both type 1 and type 2 AIT.

• As she is clinically asymptomatic, no treatment is nec-

essary at this stage (just in case her thyroid recovers) and

she can be simply followed up with repeat TFTs

Thyroid ultrasound

(Doppler) shows increased

vascularity

She is seen 3 months later with TFTs:

In type 2 AIT:

FT4

6.7 pmol/L

Thyroid antibodies are usually negative

FT3

1.6 pmol/L

CRP levels are elevated

TSH

39.2 mIU/L

Thyroid Doppler shows decreased vascularity

Clinically, she has classical symptoms of hypothyroidism.

Bridget’s tests showed

TPOAb negative

What would you do?

CRP 56 mg/L

Bridget’s TFTs are consistent with hypothyroidism and

Ultrasound Doppler decreased vascularity

she should, therefore, start treatment on thyroxine.

122

Part 2: Cases

Box 30 Amiodarone facts

• Amiodarone has a high iodine concentration (40% of

• Amiodarone-induced hyperthyroidism can develop a few

weight), which contributes to the abnormal TFTs seen

months after stopping amiodarone due to the long half-

during treatment with this drug

life of the drug

• More than a quarter of patients taking amiodarone

• Differentiating type 1 from type 2 AIT can be difficult, in

develop abnormalities in thyroid function

which case the patient should be treated for both with

• Up to 5% of patients develop clinical hyperthyroidism and

high-dose antithyroid drugs and steroids

up to 15% develop clinical hypothyroidism

CASE REVIEW

Bridget, who is on amiodarone treatment for paroxysmal

TSH). The differential diagnosis is between type

atrial fibrillation, has abnormal thyroid function with

amiodarone-induced

thyrotoxicosis

(similar

elevated levels of T4, whereas T3 and TSH are normal.

autoimmune hyperthyroidism) or type

(similar to

Amiodarone can affect the thyroid gland and cause

thyroiditis). Her investigations showed negative thyroid

hypothyroidism, hyperthyroidism and may also result in

antibodies, raised CRP and reduced thyroid gland

mildly abnormal TFTs, which have no clinical significance.

vascularity consistent with type 2 amiodarone-induced

Due to inhibition of T4 to T3 conversion in the periphery,

thyrotoxicosis. She was treated with steroids and her

amiodarone resulted in the initial abnormal thyroid

thyroid function normalized after 3 months. Subsequently,

function seen here, and this has no clinical significance.

she became hypothyroid

(low FT4 and raised TSH)

However, 18 months later Bridget developed symptoms of

secondary to thyroid tissue destruction following her

hyperthyroidism and her thyroid function was consistent

thyroiditis and was started on treatment with thyroxine.

with frank hyperthyroidism (raised T3, T4 and suppressed

KEY POINTS

• Amiodarone, which has a high iodine content, can cause

AIT type 2: similar to thyroiditis and usually

hypothyroidism (around 15% of patients), hyperthyroidism

characterized by no goitre, raised CRP levels, decreased

(around 5% of patients) and can result in abnormal

vascularity of the thyroid gland and response to steroid

thyroid function (high T4 with or without high TSH and

treatment

normal T3), which has no clinical significance

Mixed AIT: a mixture of type 1 and type 2 and is treated

• Amiodarone-induced thyrotoxicosis (AIT) can be divided

by both steroid and antithyroid agents

into

• It is preferable to stop amiodarone in AIT if at all possible

AIT type 1: similar to autoimmune hyperthyroidism and

• Amiodarone-induced hypothyroidism is simply treated

usually characterized by presence of a goitre, positive

with thyroxine replacement

thyroid antibodies, increased vascularity of the thyroid

• Patients on amiodarone treatment should be regularly

gland on Doppler examination and response to

monitored for the development of thyroid dysfunction

antithyroid drugs

Case 15

A 22-year-old man with hypertension

Stuart, who is 22 years old, is found to be hypertensive at

Sweating and heat intolerance

188/105 during routine blood pressure measurement taken

Episodes of pallor

after registering with a new GP. The patient is asymptomatic

Headaches

and there is no previous history of note. Two repeat blood

• Primary aldosteronism (symptoms of hypokalaemia)

pressure measurements in the next few days showed

Weakness

readings of 185/103 and 182/101.

Paraesthasia

Cramps

What is the differential diagnosis at

• Cushing’s syndrome

this stage?

Weight gain

The patient has high blood pressure. This can be divided

Easy bruising

into:

Abdominal striae

• Essential hypertension: majority of cases

Visual problems (in case of pituitary adenoma)

• Secondary hypertension: this should be considered

• Acromegaly

here due to the patient’s young age. Causes of secondary

Headaches

hypertension include:

Increased sweating

Renal disease: parenchymal or vascular (renal artery

Change in shoe and glove sizes

stenosis)

Visual problems

Coarctation of the aorta

Endocrine abnormalities: pheochromocytoma,

What signs would you look for during

primary aldosteronism, Cushing’s syndrome, acro-

physical examination?

megaly, associated with primary hyperparathyroidism

• Signs of renal disease

• Abdominal bruits (renal artery stenosis)

What would be your next step?

• Radio-femoral delay; weak or absent femoral pulses;

• A thorough history

cardiac murmurs (coarctation of the aorta)

• Physical examination

• Abdominal masses (pheochromocytoma)

• Signs of Cushing’s syndrome

What symptoms would you look for?

• Signs of acromegaly

• Chronic renal disease

• Signs of hypertensive retinopathy

Fatigue

Muscle cramps

The patient has a normal physical examination except for

Itchy skin

grade II hypertensive changes on funduscopy. His ECG is

• Coarctation of the aorta

shown in Fig. 57.

Symptoms of heart failure

• Pheochromocytoma

What is the significance of this ECG?

Episodes of palpitations

• It shows left ventricular hypertrophy, indicating long-

standing and severe hypertension

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

• LVH on ECG and retinal changes indicate end organ

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

damage secondary to hypertension

123

124

Part 2: Cases

What do these results indicate?

• These results rule out pheochromocytoma and chronic

renal disease as the cause of this patient’s hypertension

• Normal renal artery Doppler makes a diagnosis of

renal artery stenosis highly unlikely although it does not

conclusively rule out this diagnosis, which may require

MRA in suspicious cases

• The combination of low potassium and high bicarbon-

ate

(hypokalaemic alkalosis) is strongly suggestive of

primary aldosteronism as a cause of the hypertension in

III

this patient

• Hypokalaemic alkalosis and hypertension may also

occur in Cushing’s syndrome and this should be ruled

aVR

out if there is any clinical suspicion

What test would you request next?

• Potassium should be normalized with supplements

aVL

followed by blood tests to check:

Plasma renin activity (PRA)

aVF

Aldosterone

25.0

mm/sec

• The patient should not be on any hypertensive

Figure 57

medications that may interfere with PRA and aldoste-

What investigations would Stuart need

rone, such as:

at this stage?

ACEI

• U&Es, to rule out chronic renal disease

β-blockers

• Calcium profile

spironolactone

• CXR: may show signs of coarctation of the aorta

• If treatment of the patient is necessary while the above

• Renal ultrasound and renal artery Doppler or mag-

tests are carried out, α-blockers

(i.e. doxazosin) or

netic resonance angiography (MRA) to rule out renal

calcium channel-blockers can be used

artery stenosis

Supine measurements of aldosterone and PRA are carried

• Urinary

catecholamines

(rule

out

pheo-

out and these show:

chromocytoma)

Aldosterone

1220 nmol/L (100-500)

• If there is any suspicion of Cushing’s syndrome

PRA

0.2 pmol/ml/hr (1.1-2.7)

24 h urinary cortisol

Overnight or low-dose dexamethasone suppression

What do these results indicate?

test

The diagnosis is probable primary hyperaldosteronism

• If there is any suspicion of acromegaly

resulting in hypertension and this is supported by:

Glucose tolerance test with GH measurement

• High aldosterone levels

• Thoracic MRI or CT should be arranged if there is

• Low PRA

suspicion of coarctation of the aorta

A ratio of aldosterone/PRA >2000 is diagnostic of

primary aldosteronism.

Stuart’s tests showed:

Renal ultrasound and Doppler normal

What radiological test would you

Urinary catecholamines: normal on three occasions

request and why?

144 mmol/L

• MRI of the adrenal glands

3.0 mmol/L

• Primary aldosteronism may be due to:

5.4 mmol/L

Adrenal adenoma

(usually benign): this can be

HCO3−

29 mmol/L

treated surgically or medically

Creatinine

76 μmol/L

Adrenal hyperplasia: no role for surgical interven-

Calcium

2.3 mmol/L

tion and treatment is medical

Case 15

125

MRI shows a nodule in the left adrenal gland measuring

Hypertension is cured in only two-thirds of patients with

2.4 cm in diameter.

Conn’s syndrome following surgical removal of the

tumour and this should be made clear to the patient.

What is the most likely diagnosis?

The most likely diagnosis is Conn’s syndrome (adrenal

What medical treatment can you offer?

adenoma secreting excessive aldosterone).

• Spironolactone (aldosterone antagonist): side effects

include gynaecomastia and impotence in men, menstrual

What treatment would you advise?

irregularities in women

• Surgical removal of the adrenal adenoma is advised

• Potassium-sparing diuretic

• It should be noted that large tumours (more than 4 cm

Amiloride

in size) have a greater potential of being malignant and

Triamterene

these should always be surgically removed

The patient asks you ‘Would my high blood pressure be

cured after having surgery?’

CASE REVIEW

Stuart is a young man who is found to be hypertensive

alkalosis suggests hyperaldosteronism as a cause of

during routine examination. Subsequent measurements of

hypertension. This suspicion is confirmed by demonstrating

blood pressure confirm a diagnosis of hypertension. Due

a raised aldosterone:renin ratio and MRI imaging shows

to his young age, secondary hypertension is suspected.

an adrenal tumour consistent with a diagnosis of Conn’s

Apart from retinal hypertensive changes, his clinical

syndrome. Surgical treatment is the best option for this

examination is unremarkable. His ECG shows left

condition although it does not normalize blood pressure

ventricular hypertrophy indicating end organ damage

in all patients. Medical treatment includes the aldosterone

despite his young age. Initial investigations rule out renal

antagonist spironolactone and potassium-sparing diuretics

artery stenosis and pheochromocytoma, but hypokalaemic

(amiloride and triamterene).

KEY POINTS

• Secondary causes of hypertension should be suspected in

confirmed by demonstrating raised aldosterone/renin

young individuals and those with severe disease

activity (provided the patient is not on treatment with

• Secondary causes of hypertension include:

diuretics or agents that affect the renin-aldosterone

Kidney disease: vascular (renal artery stenosis) or

system)

parenchymal (chronic renal failure)

• Primary aldosteronism may be due to:

Endocrine disease: pheochromocytoma, primary

Adrenal adenoma (Conn’s syndrome): usually treated

aldosteronism, Cushing’s syndrome, acromegaly

with surgery

Cardiovascular disease: coarctation of the aorta

• Adrenal hyperplasia: treated medically

• Primary hyperaldosteronism should be suspected in

• Medical treatment of primary hyperaldosteronism includes:

individuals with hypertension and hypokalaemic alkalosis

Aldosterone antagonists: spironolactone

• Diagnosis of primary hyperaldosteronism is usually

Potassium-sparing diuretics: amiloride and triamterene

Case 16

A 20-year-old woman with polyuria

and polydipsia

Ivy, a 29-year-old woman, presents with a short history of

• Family history of diabetes

polyuria and polydipsia.

Family history of T1DM or autoimmunity

(i.e.

thyroid disease, pernicious anaemia) suggests a genetic

What differential diagnosis would you

predisposition to T1DM

be thinking of?

Family history of diabetes at young age not requiring

The differential diagnosis includes:

insulin or diabetes inherited in an autosomal domi-

• Diabetes mellitus

nant manner is suggestive of Maturity Onset Diabetes

• Hypercalcaemia

of the Young (MODY)

• Chronic renal failure

• Diabetes insipidus

What test would you ask the nurse to

• Psychogenic polydipsia

perform that may help to differentiate

between T1DM and T2DM?

Her blood tests done by her GP earlier showed:

Urine dipstick for ketones

Glucose

20 mmol/L

• Heavy ketonuria is consistent with T1DM

Sodium

131 mmol/L

• Absence of ketonuria does not rule out T1DM

Potassium

4.4 mmol/L

Urea

5.4 mmol/L

What else would you like to know?

Creatinine

76 mmol/L

The weight/BMI of the patient

Calcium

2.34 mmol/L

Box 31 Diabetes and BMI

What questions would you ask

this patient?

• An overweight patient with diabetes is more likely to

Ivy has high plasma glucose levels indicating a diagnosis

have T2DM

of diabetes. It is important at this stage to differentiate

• A thin patient with diabetes is more likely to have

between type 1 diabetes (T1DM) and T2DM. Questions

T1DM

to ask:

• However, T1DM can occur in obese individuals and

• How long have the symptoms of polyuria and polydip-

T2DM may be seen in thin subjects

sia been present?

A short history of symptoms (days to weeks) is sug-

gestive of T1DM

Ivy tells you that she had osmotic symptoms for 7-10 days,

A long history of symptoms (months) or no symp-

associated with 4 kg weight loss. Her sister has vitiligo but

toms is suggestive of T2DM

there is no other family history of note. Her BMI is 22 kg/m².

• History of rapid weight loss is strongly suggestive of

Her urine dipstick shows:

T1DM

Glucose 3+

Ketone 3+

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

Nitrate negative

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

WBC negative

126

Case 16

127

What is the most likely diagnosis?

control was initially very good on these doses of insulin, but

The most likely diagnosis is T1DM supported by:

4 months after diagnosis she had to drastically reduce the

• Short history of symptoms

dose of her insulin to 8 and 4 units due to recurring

• Significant weight loss

hypoglycaemic attacks.

• Thin patient

• Family history of autoimmunity (vitiligo)

Why did this happen?

The pancreas of patients with T1DM may partially

In unclear cases, can you do a blood test

recover after the initial diagnosis resulting in decreased

to help to differentiate between T1DM

insulin requirement. This is known as the honeymoon

and T2DM?

period.

• Glutamic acid decarboxylase

(GAD) and islet cell

antibodies are positive in the majority of T1DM patients

What do you need to ensure with any

(around 80%)

diabetes patient during a routine

• A negative antibody test does not rule out the diagnosis

review?

of T1DM

• Ensure adequate control of blood sugar

Measure HbA1c levels and aim for <6.5%

What treatment would you start?

Check glucose diary

Ivy should be immediately started on insulin.

• Look for signs of microvascular disease:

• Most patients can be managed on an out-patient

Eyes: retinopathy (retinal screening once a year)

basis.

Kidney: check for microalbuminuria

(request

• Admission should be considered for patients who look

urinary albumin/creatinine ratio once a year)

unwell or in the presence of abdominal pain/vomiting to

Feet: examine for neuropathy (monofilament test

rule out the possibility of diabetic ketoacidosis

and vibration sense once a year)

• Ensure prevention/treatment of macrovascular

complications:

Box 32 Insulin regimes

Treat hypertension

There are a number of insulin regimes, and the most

Treat hyperlipidaemia: patients with diabetes above

commonly used are:

the age of 40 are usually started on lipid lowering treat-

• Two injections a day with a mixture of insulin (short

ment with a statin no matter what their plasma

acting and long acting) such as:

cholesterol levels are

Insulin aspart and aspart protamine (Novorapid 30)

Antiplatelet treatment (aspirin or clopidogrel) in

Insulin lispro and lispro protamine (Humalog 25)

high risk subjects

• Insulin actrapid and isophane (M3)

Aggressive measures for prevention/treatment from

(the number indicates the percentage of short acting

macrovascular disease should be implemented in the

insulin in the mixture)

presence of microvascular complications

• Four injections a day, to include:

One injection of long acting insulin such as: insulin

isophane (Insulatard), insulin glargine (Lantus) or

What are the types of diabetes?

insulin detemir (Levemir)

The two main types of diabetes are shown in Table 20,

Three injections of short acting insulin that can be

p. 48. Traditionally, young patients with diabetes were

taken with meals: insulin aspart (Novorapid) or insulin

more likely to have T1DM. However, due to the recent

lispro (Humalog)

problem of obesity, T2DM can be now seen at a very

• Although the second regime includes more injections, it

young age (even children).

gives more flexibility and is usually preferred for

Other types of diabetes include:

younger patients with diabetes

• Maturity Onset Diabetes of the Young (MODY, up to

3% of T2DM)

Ivy is started on Novomix 30, 12 units in the morning and 6

This is a monogenic form of diabetes (due to a single

units in the evening and the dose is gradually titrated up to

gene defect)

24 and 14 units over a period of 6 weeks. Her glycaemic

Has an autosomal dominant mode of inheritance

128

Part 2: Cases

Patients are usually young and can be misdiagnosed

What is the likely diagnosis?

as having T1DM

This gentleman has T2DM supported by:

•

Latent Autoimmune Diabetes of Adults (LADA)

• High fasting plasma glucose (more than 7.0 mmol/L

An autoimmune form of diabetes occurring at an

on two occasions)

older age

• Overweight

Patients are usually slim

• Absence of symptoms

Patients are initially managed by oral hypoglycaemic

• Urine dipstick negative for ketones

agents but usually require insulin early after diagnosis

Rarely, some patients are misdiagnosed as having

(LADA is commonly a retrospective diagnosis)

T2DM, when they have a secondary form of diabetes,

•

Gestational diabetes

and, therefore, the above list of causes of secondary dia-

Occurs during pregnancy

betes should be kept in mind when assessing a new

Disappears after giving birth

patient with suspected T2DM.

Subjects with a history of gestational diabetes are at

increased risk of T2DM in the future

What medical treatment would you

•

Secondary diabetes

initiate to control his blood

Destruction of the pancreas: pancreatitis, pancreatic

glucose levels?

tumour, infiltrative disease (haemochromatosis)

None. Instead, advise the patient to:

Endocrine abnormalities: acromegaly, Cushing’s

• Change to a healthy diet

disease, pheochromocytoma, hyperthyroidism (rare)

• Regular exercise

•

Associated with genetic syndromes

• Try to lose weight

Down’s syndrome

Turner’s syndrome

Andrew implements your suggestions and is reviewed 3

Lawrence-Moon-Biedl syndrome

months later. He has lost 4 kg in weight and his HbA1c is

Prader-Willi syndrome

now 6.8%.

•

Drug-induced

Steroids

What would you do?

Ivy’s father, Andrew aged 62, presents a few months later to

Congratulate Andrew and encourage him to continue

his GP, stating that his daughter checked his blood sugar

with his programme of:

with her glucose meter and found it to be elevated. He is

• Diet

asymptomatic and overweight with a BMI of 29.9. He has

• Exercise

no past medical history of note and his urine dipstick shows:

Glucose 3+

He is reviewed 18 months later. Despite continuing with diet

Ketone trace

and exercise, his HbA1c has risen to 8.1%.

Nitrate negative

WBC negative

What would you do to control his

What test would you request?

blood sugar?

Fasting plasma glucose on two occasions.

Andrew needs to be started on antidiabetic treatment.

• Diabetes is usually confirmed by checking fasting

The preferred first-line agent in overweight T2DM

glucose twice, particularly in individuals who are

patients is metformin (Glucophage).

asymptomatic

• In subjects with classical symptoms, one glucose

Andrew is well on metformin for 2 years but his diabetes

sample is enough to confirm the diagnosis

control subsequently deteriorates and his HbA1c rises to

8.9%.

His blood tests showed:

Fasting glucose: 10.3 and 11.6 mmol/L

What would you do now?

HbA1c: 8.6%

Andrew can be started on one of the following drugs:

U&Es normal

• A sulphonylurea: this group of drugs stimulate insulin

Case 16

129

Box 33 Common side effects of metformin

Treatment of

type 2 diabetes

The most common side effects of metformin are

gastrointestinal and include:

• Nausea

• Vomiting

• Bloating

1st line

Diet and exercise

• Diarrhoea

These side effects can usually be avoided by initiating a

small dose of the drug and gradually titrating to higher

2nd line

Metformin

doses. A long acting preparation of metformin

(Glucophage SR) seems to be associated with fewer side

effects.

The most serious side effect of metformin is lactic

Suplhonylureas or

acidosis. This occurs in the presence of:

3rd line

thiazolidinediones

• Renal failure

• Advanced heart failure

• Septicaemia

Suplhonylureas or

• Therefore, metformin should be avoided in patients with

4th line

thiazolidinediones

a creatinine above 150 μmol/L or in those with

advanced heart failure. Metformin should also be

stopped in patients who become septic.

5th line

Insulin

secretion by the pancreas. Commonly used drugs

include:

Can be used at any

Gliclazide

of the above stages

Slimming tablets

Glimepiride

• A thiazolidinedione: this group of drugs act as insulin

Figure 58 Treatment of type 2 diabetes. Metformin is usually

sensitizers and seem to have cardioprotective properties.

the first-line agent except in those with contraindication or

Commonly used drugs include:

intolerance. Oral hypoglycaemic agents can be used in

Rosiglitazone

combination therapy (even as triple therapy). Insulin can be

used in combination with metformin or a sulphonylurea and

Pioglitazone

even pioglitazone. New agents that have been recently

What are the two main drawbacks

released include glucagon-like peptide analogues (injections)

of sulphonylureas?

and DPP-4 inhibitors (oral), which can be used as second- to

fourth-line agents.

• Weight gain due to stimulation of insulin secretion

• Hypoglycaemia

• Pregnancy,

oral

hypoglycaemics

are

What is the main contraindication for

contraindicated

the use of thiazolidinediones?

• Heart failure is the main contraindication as these

Apart from antidiabetic agents, what

agents may cause fluid retention, thereby worsening

other drugs are available that may help

existing heart failure

to control blood sugar?

When do you use insulin in type

• Slimming tablets such as:

2 diabetes?

Sibutramine

• Failure of oral therapy

Orlistat

• Hospital admission

Rimonabant

Infection

• Acarbose which inhibits glucose absorption

Myocardial infarction

Treatment of type 2 diabetes is summarized in Fig. 58.

130

Part 2: Cases

CASE REVIEW

Ivy is a young woman presenting with a short history of

found to be elevated confirming a diagnosis of diabetes.

polyuria and polydipsia. Her blood tests are consistent

Andrew is overweight, asymptomatic with no ketonuria

with a new diagnosis of diabetes. A detailed history is taken

consistent with a diagnosis of type 2 diabetes. Andrew

to establish the type of diabetes. A short history of

initially manages to control his diabetes with diet, exercise

symptoms in a lean patient, weight loss, a family history of

and weight loss. His diabetes control deteriorates

autoimmunity and ketonuria all suggest a diagnosis of type

months later and he is started on metformin treatment,

1 diabetes. In unclear cases, autoantibody measurement

which is the first-line agent in overweight T2DM patients.

and insulin levels can be helpful to distinguish between

His diabetes control deteriorates again and, traditionally,

different types of diabetes. Ivy is started on insulin

either a sulphonylurea or a thiazolidinedione can be given

treatment, which controls her diabetes well. However, her

at this stage. Newer agents, including GLP-1 analogues and

insulin requirements subsequently decrease due to partial

DDP-4 inhibitors, can also be used as second-, third- or

recovery of the pancreas, often known as the honeymoon

fourth-line treatments.

period, which is a temporary phenomenon.

It should be remembered that the majority of diabetes

Andrew, Ivy’s father, measures his blood sugar using his

patients develop vascular complications and it is important

daughter’s glucose meter and his capillary glucose is found

to treat a cluster of risk factors, rather than blood sugar

to be elevated. He is asymptomatic, overweight and his

alone, in these patients to prevent long-term complications.

urine test shows absence of ketonuria. His fasting glucose

These risk factors include hypertension, microalbuminuria,

is checked on two occasions (as he is asymptomatic) and

dyslipidaemia and increased thrombosis potential.

KEY POINTS

• Diabetes mellitus, a common condition, is characterized

• Type 2 diabetes is characterized by:

by high blood glucose

Occurrence in the older population (peak age 60 years

• Diagnosis of diabetes

but can occur at any age) and usually in individuals

Elevated fasting glucose (>7 mmol/L) or postprandial

who are overweight

glucose (>11.1 mmol/L) twice in the absence of

Long history of symptoms (months and even years) or

symptoms or once in the presence of symptoms

no symptoms at all

Glucose tolerance test is warranted in unclear cases and

No history of weight loss and no ketonuria

in those with impaired fasting glucose (>6 mmol/L)

• Autoantibody testing (positive in the majority of type 1

Most cases of diabetes (around 80-90%) are due to

diabetes) and fasting insulin levels (low or undetectable in

type 2 diabetes, usually secondary to increased insulin

type 1 diabetes) can help to distinguish type 1 from type

resistance, a condition closely associated with obesity

2 diabetes

In a minority, diabetes is due to specific autoimmune

• Treatment

destruction of β cells (type 1 diabetes)

Type 1 diabetes is treated with insulin and the most

Less common causes of diabetes include generalized

common regimes include: twice daily injections of

pancreatic destruction (chronic inflammation, alcohol,

mixed insulin (short acting and intermediate acting),

trauma), endocrine conditions (acromegaly, Cushing’s

four daily injections of long acting insulin (once) and

syndrome) and other rare conditions

short acting insulin with meals, insulin pump

• Type 1 diabetes is characterized by:

(continuous insulin infusion)

Occurrence in the younger population (peak age 12

Type 2 insulin is treated in stepwise manner: step 1, diet

years but can occur at any age) and usually in

and exercise; step 2, start metformin treatment; step 3,

individuals who are not overweight

add in a sulphonylurea or thiazolidinedione; step 4,

Short history of osmotic symptoms (days to weeks)

triple oral hypoglycaemic agent therapy; step 5, add in

Rapid weight loss

or switch to insulin treatment. Others: new agents

Ketonuria

(GLP-1 analogues and DDP-4 inhibitors can be used in

Case 17

A 78-year-old man with pain in

the leg and knee

Graham, aged 78, has been undergoing investigations for

How would you rule out osteomalacia

pain in his right hip and knee. Routine blood tests showed:

in this patient?

13.4 g/L

Osteomalacia is associated with:

WBC

8.7 × 10⁹/L

• Low or low-normal calcium

Plats

387 × 10⁹/L

• Low vitamin D

139 mmol/L

• High PTH

4.4 mmol/L

• High AP

Urea

4.5 mmol/L

Therefore, calcium profile, vitamin D and PTH should

Creat

77 μmol/L

be requested in this patient.

Glu.

5.4 mmol/L

ALT

28 U/L

Calcium profile, vitamin D and PTH are all in the normal

1370 U/L

range.

GGT

31 U/L

Bil

16 μmol/L

What imaging would you request in this

patient?

How do you interpret these results and

• X-ray of the hip and knee

what would you do next?

• Isotope bone scan

• The only abnormality here is a high alkaline phospha-

tase (AP) with otherwise normal LFTs

Figure 59 shows a pelvic X-ray and bone uptake scan.

• This suggests that raised AP is from a bony and not

a liver origin

What abnormalities can you identify

• If in doubt:

and what is the diagnosis?

AP isoenzymes can be requested that can differenti-

• The X-ray shows mixed lytic and sclerotic bone lesions

ate between AP of liver and bony origin

in the pelvic bone (particularly on the right)

A raised AP with normal gamma glutamyl transpep-

• The bone scan shows multiple areas of increased uptake

tidase (GGT) further suggests that it is from a bony

The likely diagnosis here is Paget’s disease.

origin

What are the common symptoms of

What are the causes of raised bony AP?

Paget’s disease?

• Osteomalacia

• Up to 90% of individuals are asymptomatic and the

• Fractures

disease is picked up during routine investigations for

• Bony metastasis

another pathology

• Paget’s disease

• Symptoms include:

• Growing children and adolescents

Bone pain

Bone deformity: bowing of the tibia is a classical

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sign

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

Nerve compression (may cause deafness)

132

Case 17

133

What are the signs of Paget’s disease?

• Bone deformity (cranial and tibial bone deformity are

classical features) (see Fig. 60, colour plate section, and

Fig. 15)

• Warm bones due to the formation of collateral

circulation

• A bruit can be heard over the bone secondary to extra

blood flow

• Deafness (nerve compression)

• Cranial nerve palsies at the base of the skull

• Spinal cord compression

• Fractures

• Osteogenic sarcoma: rare and serious complication

(a)

Would you treat Graham and why?

Graham needs to be treated as he is:

• Symptomatic

• Has a high AP

What is the best treatment for this

condition?

Bisphosphonates are currently the best treatment option

for this condition.

How do you monitor response

to treatment?

• Improvement in symptoms

• Reduction in AP levels

What happens to calcium levels in

patients with Paget’s disease?

Calcium levels are usually normal in uncomplicated

Paget’s disease.

(b)

Figure 59 (a) X-ray of the hip lesions. (b) Bone uptake scan.

What is the long-term management of

this condition?

• Monitor for the development of complications

• Repeat bisphosphonate treatment as necessary

CASE REVIEW

Graham, who is 78 years old, presents with pain in his knee

bony destruction with new bone formation in the pelvis,

and leg. Initial investigations show a raised alkaline

whereas increased uptake in multiple bones is demonstrated

phosphatase with otherwise normal liver function tests.

on an uptake scan. These findings are consistent with a

Calcium profile, vitamin D and parathyroid hormone

diagnosis of Paget’s disease. The best treatment for

levels are normal ruling out osteomalacia as a cause for

symptomatic Paget’s disease is bisphosphonate that can be

raised alkaline phosphatase. Further investigations show

given orally or intravenously.

Case 18

A 32-year-old woman with a lump in

the neck

A GP refers Sharon with the following letter:

Malignant thyroid nodules are usually cold

This 32-year-old woman has noticed a lump in her neck

(non-functioning)

that moves with swallowing. An ultrasound examination

confirmed this to be a thyroid nodule measuring 2 × 3 cm.

What would be your next step?

I would be most grateful for your advice regarding the

• Physical examination

management of this patient’s thyroid condition.

What features would you be looking for

What specific questions would you like

during the physical examination?

to ask the patient?

• Establish the patient’s thyroid status

Questions asked should concentrate on trying to differ-

• Neck examination to determine the characteristics of

entiate between a benign and malignant thyroid nodule.

the nodule and feel for lymphadenopathy. Findings sug-

These should include the following:

gestive of malignancy include:

• How long has the thyroid mass been there?

Firm or hard nodule

A long history

(years) makes it unlikely to be

Fixation to adjacent tissue

malignant

Presence of lymphadenopathy

• Has it been growing?

A mass that has not grown over the years is more

Sharon tells you that she noticed the nodule around 12

likely to be benign

months ago and thinks that it may have grown in size in the

• Any associated symptoms?

past 2 months or so. On examination, the patient is clinically

Hoarseness and/or dysphagia may indicate a malig-

euthyroid and neck palpation reveals a firm solitary thyroid

nant condition spreading beyond the thyroid gland

nodule with no fixation to adjacent tissue and she has no

• Previous history of radiation

(particularly in

palpable lymph nodes. TFTs showed:

childhood)

FT4

19.3 pmol/L

May raise the suspicion of a malignant condition

TSH

1.8 mU/L

• Family history of thyroid cancer increases the risk of

malignancy in a thyroid nodule

What would be your next step?

• Symptoms of hyperthyroidism

Fine needle aspiration of the nodule.

If the patient is thyrotoxic, the nodule may be hot

(i.e. overactive), making it less likely to be malignant

Cytology of the fine needle aspiration of the thyroid is

• It is worth noting:

consistent with a papillary carcinoma.

Thyroid nodules are more common in women but

more likely to be malignant in men

What is the best treatment option for

Thyroid nodules are more likely to be malignant if

this patient?

the patient is younger than 20 or older than 60

• Surgery (total thyroidectomy)

The rate of malignancy in thyroid nodules is usually

• Radioiodine treatment is usually arranged after surgery

low (less than 10%)

for the ablation of any possible thyroid remnants

The patient undergoes thyroidectomy followed by

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

radioiodine ablation. There is no evidence of tumour

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

spreading beyond the thyroid gland.

135

136

Part 2: Cases

• Therefore, the dose of thyroxine replacement should

Box 34 Different types of thyroid cancer

be increased to suppress TSH levels, without causing sig-

nificant clinical thyrotoxicosis

• Papillary carcinoma

• TSH suppression is not necessary in patients with

Commonest (70-80%)

Age at presentation: usually 30-50

medullary thyroid cancer or those with lymphoma, as the

Prognosis: good

malignant cells are not TSH responsive (they are not

Treatment: thyroidectomy and radioiodine remnant

thyroid follicular cells)

ablation

• Follicular carcinoma

How would you monitor patients with

Less common (15%)

treated thyroid cancer?

Age at presentation: usually 40-50

• Regular physical examination

Prognosis: good

• Thyroglobulin measurement in the plasma:

Treatment: thyroidectomy and radioiodine remnant

Detection of thyroglobulin in a patient who had pre-

ablation

vious thyroidectomy and ablation therapy indicates the

• Anaplastic carcinoma

presence of thyroid tissue

Rare (5%)

Age at presentation: usually 60-80

This is particularly important if thyroglobulin

Prognosis: poor

becomes measurable following a period when levels of

Treatment: surgery and chemotherapy

this protein were undetectable

• Lymphoma

Uncommon

If our patient was both clinically and

Age at presentation: usually in women >40, with a

biochemically thyrotoxic on

background of Hashimoto’s thyroiditis

presentation, what would you have

Prognosis: variable

done?

Treatment: radiotherapy/chemotherapy

• In a patient who is thyrotoxic and with a thyroid

• Medullary thyroid carcinoma

nodule, we need to establish whether:

Rare: can be familial

The patient has a toxic (hot) nodule causing thyro-

Age at presentation: any age (may even occur in

children particularly as part of multiple endocrine

toxicosis (unlikely to be malignant)

neoplasia type 2)

The patient has an overactive thyroid

(Graves’

Prognosis: variable

disease or toxic goitre) with a cold nodule

(cold

Treatment: surgery

What is the prognosis in this case?

Prognosis is excellent with more than 95% cure rate in

developed countries.

After surgery and radioiodine ablation, Sharon is treated

with thyroxine replacement with a dose of 150 mcg/day. Her

TFTs showed:

FT4

20.3 pmol/L

TSH

1.2 mIU/L

What would you do?

• TSH stimulates the growth of benign as well as malig-

nant thyroid cells

• Therefore, in patients post-thyroidectomy for papil-

lary or follicular cancer, thyroxine replacement should

aim to suppress TSH without inducing clinical

thyrotoxicosis

Figure 61 Thyroid uptake scan.

Case 18

137

nodules are more likely to be malignant in patients

What are the complications

with Graves’ disease)

of thyroidectomy?

• The patient should, therefore, undergo a thyroid uptake

• Hypothyroidism

scan to differentiate between the two above possibilities

• Hypocalcaemia (secondary to damage of the parathy-

roid glands)

Figure 61 is a thyroid uptake scan from a thyrotoxic patient.

• Recurrent laryngeal nerve damage

(resulting in a

hoarse voice)

What does it show?

• Local haemorrhage

• A hot nodule (increased uptake), in the right lobe of

• Wound infection

the thyroid

• Keloid formation

CASE REVIEW

Sharon, a young woman, is referred by her GP for advice

scan is helpful to distinguish between cold (non-functional)

regarding the management of a thyroid nodule. This is a

and hot (producing excess thyroid hormones) nodules in

common condition and fortunately most thyroid nodules

individuals who are thyrotoxic. Sharon was found to be

are benign. Clinical features suggestive of malignancy

euthyroid and, therefore, she has undergone a fine needle

include a fast growing and hard nodule, hoarseness of voice

aspiration of the thyroid nodule, which was consistent with

or dysphagia and the presence of cervical lymphadenopathy.

a papillary thyroid carcinoma. Consequently, she was

Special care should be taken in individuals with a previous

referred for surgery followed by radioiodine ablation,

history of irradiation or a family history of thyroid cancer.

which is a standard treatment regime for papillary thyroid

Thyroid nodules can be functional, secreting excess thyroid

carcinoma. The prognosis for this type of thyroid cancer,

hormone, which are very rarely malignant, whereas non-

which is the commonest, is very good with a cure rate

functional nodules may be malignant. A thyroid uptake

approaching 95%.

KEY POINTS

• Thyroid nodules are common, with a prevalence rate of

(producing excess thyroid hormones). A toxic nodule is

5-30% according to the population studied (prevalence in

usually benign, whereas cold nodule in an individual with

the UK is around 10%)

Graves’ disease carries a significant risk of malignancy

• Only a minority of thyroid nodules are cancerous and

• Thyroid cancers include:

these are usually non-functional

Papillary (75%)

• Toxic thyroid nodules are very unlikely to be malignant

Follicular (10%)

• Special care should be taken in individuals with a previous

Medullary (5%)

history of irradiation or a family history of thyroid cancer

Anaplastic (5%)

(malignancy more likely)

Lymphoma (5%)

• Clinical features of malignant thyroid nodules include:

• The prognosis of papillary and follicular thyroid cancers is

Fast growing, hard nodules and skin fixation over the

usually good, whereas anaplastic cancers carry a very poor

nodule

prognosis. Medullary cancers and lymphomas have a

Presence of cervical lymphadenopathy

variable prognosis

Hoarseness of voice

• Treatment of thyroid cancers involves:

Dysphagia

Surgery and radioiodine ablation therapy (papillary and

• In euthryoid individuals, the first-line investigation of a

follicular)

thyroid nodule is fine needle aspiration

Surgery (medullary)

• In an individual with thyrotoxicosis and thyroid nodule(s),

Radiotherapy and chemotherapy (lymphoma)

thyroid uptake scan should be arranged to investigate

Palliative radiotherapy (anaplastic)

whether the nodule(s) are cold (non-functional) or hot

• It important to give a high dose of thyroxine replacement

Continued

Case 19

A 26-year-old with headaches

and hypertension

Omar, who is 26 years old, is seen by his GP because of

• Abdominal MRI: sensitive at detecting these tumours

recurrent headaches and generally feeling unwell. His blood

• CT: less sensitive at detecting adrenal tumours

pressure was found to be elevated at 195/100.

• Radiolabelled meta-iodobenzylguanidine

(MIBG)

scan: this is positive in around three-quarters of pheo-

What would you do next?

chromcytomas and may detect tumours not visualized

Secondary causes of hypertension should be sought

by MRI

(detailed in Case 15) and appropriate history and physi-

cal examination should be undertaken.

The patient is found to have a large left adrenal tumour

measuring 5 cm in diameter. The surgeon would like to

The patient tells you that for the past 6 months, he has

immediately remove the tumour.

been suffering from increased sweating and heat

intolerance, severe headaches and episodes of palpitations

Do you agree?

associated with pallor.

• No, because a surgical procedure in a patient with a

pheochromocytoma may precipitate a hypertensive

From the history, what would you like

crisis

to rule out as a cause for this patient’s

• The patient should be prepared for surgery with appro-

hypertension?

priate antihypertensive therapy

Given the:

• Symptoms

What antihypertensive is used to treat

• Young age

these patients?

• Severe hypertension

• Patients are usually treated with α-blockers

A pheochromocytoma should be ruled out.

(phenoxybenzamine)

• Before surgery, i.v. phenoxybenzamine is used for 3

What test would you request?

days to ensure complete α-blockade

Three

24-h urine collections for catecholamine and

• β-blockers can only be used once the patient is fully

metanephrine measurement (see Part 1, p. 33).

α-blocked

Urinary catecholamines were found to be two- to threefold

The patient undergoes surgery and the tumour is

above the upper end of normal in all three 24-h urinary

successfully removed with restoration of normotension off

collections.

any antihypertensive treatment. However, during routine

tests, the patient’s calcium is found to be elevated at

What would you do next?

3.2 mmol/L.

The results are highly suggestive of a pheochromocy-

toma. The next step should be directed at localizing the

What test would you request next?

tumour. Imaging techniques include:

Any patient with hypercalcaemia should have their PTH

levels checked.

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

The patient’s PTH levels are elevated at 14.3 pmol/L (normal

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

range 1-6.1 pmol/L).

139

140

Part 2: Cases

What is the cause of hypercalcaemia?

Multiple neurofibromas

(Fig.

62, colour plate

Raised calcium with raised PTH is indicative of primary

section)

hyperparathyroidism.

Café au lait spots

Iris Lisch nodules

What diagnosis would you suspect in

Endocrine abnormalities including pheochromo-

this case?

cytoma

The combination of pheochromocytoma and primary

hyperparathyroidism should raise the suspicion of mul-

Does a pheochromocytoma tumour

tiple endocrine neoplasia type II (MEN II).

always occur in the adrenal gland?

No, 10% can be extra-adrenal.

What other endocrine organ would you

like to examine in this patient and why?

Can a pheochromocytoma occur in both

The thyroid gland should be examined in this patient as

adrenal glands?

MEN II includes:

Yes, 10% are seen in both adrenal glands.

• Medullary thyroid cancer (MTC): often the initial pre-

sentation of this familial condition and it occurs in all

Is pheochromocytoma a benign tumour?

individuals involved

Most are, but 10% can be malignant.

• Pheochromocytoma: usually occurs later in up to half

Box 35 Rule of 10 when dealing with a

the affected individuals

pheochromocytoma

• Hyperparathyroidism: occurs in around a quarter of

the affected subjects

The rule of 10 refers to the fact that approximately 10%

of pheochromocytomas are:

The patient is found to have a large thyroid nodule.

• Familial

• Extra-adrenal

What blood test(s) may help you to

• Bilateral

confirm your suspicion?

• Malignant

• The patient probably has a medullary thyroid

carcinoma

What is MEN I?

• Serum calcitonin can be requested, which is usually

MEN I is also an autosomal dominant condition second-

elevated in patients with MTC

ary to a mutation in the menin gene. It involves the

association of:

What is the aetiology of MEN II?

• Parathyroid hyperplasia

• MEN II is due to a mutation in the ret proto-oncogene,

• Pancreatic endocrine tumours, usually:

which is a transmembrane receptor

Gastrinoma

• Any patient who is suspected to have MEN II should

Insulinoma

be screened for a ret proto-oncogene mutation

• Pituitary adenomas, usually:

• As MEN is an autosomal dominant condition, other

Prolactinoma

family members should also be screened for the mutation

Acromegaly

• MEN I is best remembered by PPP:

Are all pheochromocytomas familial?

Parathyroid

No, only 10% are familial (some would argue up to 20%

Pancreas

are familial). Familial pheochromocytomas can be seen

Pituitary

in:

• MEN II is best remembered by TAP:

• MEN II

Thyroid

• Von Hippel-Lindau disease, which includes:

Adrenal

CNS and retinal haemangioblastomas

Parathyroid

Pheochromocytoma

Patients and their relatives with MEN I or MEN II

Renal cysts and carcinoma

should be managed in specialized endocrine clinics with

• Neurofibromatosis type I, which includes:

the help of a geneticist.

Case 19

141

CASE REVIEW

Omar, a young man, visits his doctor with episodes of

avoid a hypertensive crisis, which may occur during the

headaches, increased sweating, palpitations and is found to

operation. After appropriate medical management, Omar

have significant hypertension. These symptoms raise the

undergoes successful adrenal surgery but his calcium and

possibility of pheochromocytoma as the cause of his

PTH levels are found to be elevated after the operation,

hypertension (secondary hypertension is discussed in Case

indicating a diagnosis of primary hyperparathyroidism.

15). Further investigations demonstrate high levels of

The association of pheochromocytoma and primary

urinary catecholamines, indicating a diagnosis of

hyperparathyroidism should raise the suspicion of multiple

pheochromocytoma. Imaging of the adrenal shows a 5-cm

endocrine neoplasia type II. This diagnosis is further

adrenal mass and the surgeon wants to undertake

supported by the presence of a thyroid nodule, likely to be

immediate surgery. However, Omar should be treated with

a medullary carcinoma, in which case plasma calcitonin

α-blockers prior to surgery to lower the blood pressure and

levels are elevated.

KEY POINTS

• Individuals with severe hypertension, particularly the

Headaches and visual disturbances

young, should be investigated for the possibility of

• The rule of 10 in pheochromocytoma:

secondary hypertension (see Case 15)

Bilateral in 10%

• Pheochromocytomas are rare medullary adrenal tumours

Extra-adrenal in 10%

and a cause of hypertension in less than 0.1% of cases

Malignant in 10%

• Pheochromocytomas may be an isolated condition or part

• Diagnosis of pheochromocytoma is made by

of/associated with:

demonstrating raised urinary catecholamines and/or

MEN type II

metanephrines in the urine

Neurofibromatosis type I

• Surgical treatment is curative in the majority of patients.

Von Hippel-Lindau syndrome

Blood pressure should be controlled before surgery and

• Clinical presentation of pheochromocytoma includes:

α-blockers are given prior to the introduction of other

Hypertension sometimes with postural hypotension

antihypertensive agents. Intravenous phenoxybenzamine

Episodes of palpitations and sweating

is given for 3 days before surgery to ensure full

Flushing or pallor

α-blockade

Case 20

Sweating, nausea and hand tremor in

a 24-year-old woman

Eleanor, a thin 24 year old woman, is seen at clinic with a

What would you do next?

few weeks’ history of episodes of sweating, sometimes

This suggests that the cause of this patient’s symptoms is

associated with hand tremor and feeling nauseous. The

hypoglycaemia, which may be due to:

symptoms are particularly pronounced in the morning,

•

Insulinoma

frequently occur after exercise and are always relieved by

Usually a pancreatic tumour secreting insulin

eating.

(benign in 85% of cases)

Diagnosis is made by demonstrating raised insulin

What differential diagnosis would you

levels and C peptide in the presence of

think of at this stage?

hypoglycaemia

Sweating can be due to a number of conditions

•

Drug-induced

including:

Insulin: injection of insulin in a non-diabetic indi-

• Thyrotoxicosis

vidual results in hypoglycaemia, in which case plasma

• Pheochromocytoma

levels of insulin will be high but C peptide will be

• Carcinoid syndrome

undetectable, in contrast to a patient with insulinoma.

• Menopause

Insulin injection can be seen in: self-injection, patients

• Hypoglycaemia

with psychiatric problems

(attention seeking and

• Psychological

trying to commit suicide); and injection by others

(possible criminal intent)

What would you do next?

Sulphonylurea

(both insulin and C peptide are

A detailed history is essential concentrating on symptoms

elevated)

of:

Alcohol (due to impairment of gluconeogenesis)

• Thyrotoxicosis (see Case 2)

•

Hormonal deficiencies:

• Pheochromocytoma (see Case 19)

Hypopituitarism

• Carcinoid syndrome (see Case 24)

Addison’s disease: tiredness, history of pigmentation

• Early menopause: if periods are regular, this diagnosis

(due to excessive ACTH secretion), weight loss and

is unlikely

gastrointestinal symptoms

(nausea and vomiting,

• Hypoglycaemia: the fact the symptoms are relieved by

abdominal pain, diarrhoea, dizziness and postural

eating suggests that this may be a possibility

hypotension)

• Psychological: this is only considered once the above

•

In severely ill patients:

possibilities are ruled out

Organ failure (acute liver failure)

Infection (septicaemia, malaria)

Eleanor further tells you that her brother has type 1 diabetes

•

Postprandial

and in view of this her GP checked her fasting blood

Usually postgastrectomy

(dumping syndrome):

glucose, which was found to be low at 2.2 mmol/L.

rapid glucose absorption due to fast gastric emptying

leads to excessive insulin secretion resulting in hypo-

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

glycaemia 1-3 h after eating

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

•

Rare causes

142

Case 20

143

Autoimmune: insulin receptor activating antibodies

There is a family history of autoimmunity, and,

Mesenchymal tumours secreting insulin-like growth

therefore, Addison’s disease is a possibility

factors

Blood tests performed by the GP 10 days earlier showed:

What are the symptoms of

Sodium

131 mmol/L

hypoglycaemia and what are

Potassium

5.2 mmol/L

they due to?

Bicarbonate

19 mmol/L

These can be divided into:

Urea

4.6 mmol/L

• Adrenergic

Creatinine

76 μmol/L

Sweating

Calcium

2.62 mmol/L

Tremor

Palpitation

What is a possible diagnosis in this

Pallor

patient? What signs would you

• Neuroglycopenic (more likely to occur with prolonged

look for?

hypoglycaemia)

The patient has the following symptoms:

Poor concentration

• Tiredness

Confusion

• Weight loss

Irritability and uncharacteristic violent behaviours

• Reduced appetite and nausea

Seizures and coma in severe and more prolonged

• Probably postural hypotension

cases

• Blood tests show:

Fasting hypoglycaemia

On further questioning, Eleanor categorically denies insulin

Hyponatraemia

injection or sulphonylurea (SU) ingestion and her alcohol

Hyperkalaemia

intake is less than 5 units a week. She has been feeling very

Low bicarbonate

tired for a few weeks, and has lost a stone in weight due to

Mild hypercalcaemia

reduced appetite and nausea. She has also been feeling

A possible diagnosis is Addison’s disease, which can be

dizzy, particularly when getting out of bed first thing in the

associated with the symptoms and the electrolyte abnor-

morning.

malities listed above.

Signs to look for include:

How would this information help you in

• Postural hypotension

the diagnosis?

• Pigmentation: seen only in primary hypoadrenalism

Insulinoma is less likely as this condition is associated

(due to raised ACTH):

with weight gain; high insulin levels and hypoglycaemia

Areas exposed to pressure (elbows, knees and under

result in frequent snacking.

bras)

• Drugs

Palmar creases

There is nothing in the history to suggest insulin/SU/

Scar tissue

alcohol as a cause of her hyperglycaemia

Mucosa

However, most patients injecting insulin/taking SU

deny ever doing so, often making the diagnosis a chal-

On checking the blood pressure, a postural drop from

lenging task

110/70 to 90/55 is noted. Eleanor has clear pigmentation

• The patient is not severely ill (which would suggest

in the oral mucosa and palmar creases.

organ failure or septicaemia as the cause for her

symptoms)

• Hypoadrenalism

(primary or secondary) is a

What tests would you request next?

possibility:

• Short synacthen test: serum cortisol is checked at

Dizziness first thing in the morning is suggestive of

0 min and 30 min

postural hypotension, which is not infrequently seen

• ACTH levels

in hypoadrenalism (more common in primary hypo-

• Plasma renin activity

adrenalism due to defective secretion of aldosterone)

• Aldosterone

144

Part 2: Cases

Her blood tests showed:

What tests can be requested to

Synacthen test:

establish the aetiology of this

0 min cortisol

76 nmol/L

patient’s hypoadrenalism?

30 min cortisol

110 nmol/L

• Serological

ACTH 330 ng/L (normal range 10-80 ng/L)

Adrenal autoantibodies, which are positive in most

Aldosterone

40 pmol/L (supine 100-500 pmol/L)

patients with autoimmune hypoadrenalism

PRA

11.1 pmol/mL/h (supine 1.1-2.7 pmol/mL/h)

• Radiological

CT or MRI of the adrenals

What is the diagnosis?

Adrenal enlargement can be seen in tuberculosis,

• The patient has a highly subnormal cortisol response

infiltrative or metastatic disease

to short synacthen test

Adrenal atrophy is seen in autoimmune

• High ACTH

hypoadrenalism

• Low aldosterone

• Elevated PRA

Adrenal antibodies are positive and a diagnosis of

The diagnosis is, therefore, primary hypoadrenalism.

autoimmune hypoadrenalism is made.

What treatment would you start and

what precautions would you give

the patient?

• Glucocorticoid replacement

Cortisol replacement divided into two or three daily

doses

Box 36 Causes of primary hypoadrenalism

• Mineralocorticoid replacement

Fludrocortisone

• Autoimmune: the commonest cause in Western society

• The patient should be advised to double the dose of

(more than two-third of cases)

steroids for a few days in case of a mild illness (i.e. cold

• Vascular event: infarction or haemorrhage into the

adrenal glands:

or flu)

Antiphospholipid syndrome

• If the patient is more severely ill, i.m. or i.v. steroids

Warfarin treatment

may be required

Meningococcal septicaemia (Waterhouse-Friedrichson

• The patient should be given an ampoule of hydrocor-

syndrome)

tisone to inject in cases of emergency (i.e. unable to take

• Infection

oral steroids due to vomiting)

Tuberculosis

Fungal: histoplasmosis, cryptococcosis

The patient is admitted 3 months later with:

Opportunistic infections: particularly in patients with

Abdominal pain

AIDS

Diarrhoea

• Malignant metastatic disease

Severe dizziness and low blood pressure at 60/40 mmHg.

• Congenital adrenal hyperplasia

• Inherited disorders of fatty acid metabolism

(adrenoleucodystrophy)

What would you do?

• Iatrogenic

The likely diagnosis is acute adrenal insufficiency. The

Prolonged use of steroids followed by sudden

patient should immediately be given:

withdrawal (adrenal glands may take some time to

• Intravenous steroids

recover after suppression of function due to external

• Intravenous fluids

steroids)

In clinical practice, any patient with unexplained

Ketoconazole: can suppress cortisol production (this

hypotension should be given a dose of hydrocortisone

drug is used to treat Cushing’s syndrome)

after taking a blood sample for random cortisol

Surgical adrenalectomy

measurement.

Case 20

145

CASE REVIEW

Eleanor is a young woman with a few weeks’ history of

confirmed by demonstrating an abnormal synacthen test,

episodes of sweating, hand tremor and feeling nauseous.

low aldosterone, together with elevated ACTH and plasma

These symptoms seem to occur in the morning or after

renin activity. Positive adrenal antibodies indicate

exercise and are always relieved by eating, raising the

autoimmune hypoadrenalism as the cause of adrenal

possibility of hypoglycaemia as the cause. Hypoglycaemia

failure, and this fits with a family history of autoimmunity.

may be due to insulinoma, which is usually associated with

The patient should be treated with a combination of

weight gain due to frequent snacking, excess alcohol, drugs

glucocorticoid and mineralocorticoid replacement and

(sulphonylurea

abuse,

insulin

injections)

and

special precautions to double the dose of steroids in case

hypoadrenalism. The latter diagnosis is suspected due to

of a mild illness and to give intravenous or intramuscular

symptoms of tiredness and weight loss as well as typical

steroids in case of severe illness or if unable to take steroids

electrolyte abnormalities (hyponatraemia, hyperkalaemia

orally (i.e. vomiting). Eleanor is admitted 3 months later

with mildly low bicarbonate). In addition to confirming

with postural hypotension and gastrointestinal symptoms,

morning hypoglycaemia, Eleanor is found to have increased

suggesting acute adrenal insufficiency, also known as an

pigmentation in oral mucosa and palmar creases as well as

adrenal crisis, which should be treated urgently with

postural hypotension, making the diagnosis of primary

intravenous fluid and glucocorticoid.

adrenal failure a strong possibility. This suspicion is

KEY POINTS

• Hypoglycaemia should be suspected in individuals with

Postural hypotension

episodes of nausea, hunger, sweating and tremor,

Pigmentation of skin and buccal mucosa (primary

particularly if symptoms are relieved by eating

hypoadrenalism)

• Causes of hypoglycaemia include:

• Causes of primary hypoadrenalism include

Alcohol-induced

Autoimmune (majority of cases in the Western world)

Insulinoma

Long-term steroid treatment

Hypoadrenalism (primary or secondary)

Infection (tuberculosis, fungal): particularly in the

Drug-induced: insulin or sulphonylurea

immunocompromised)

Reactive hypoglycaemia (occurs post meal, usually after

Vascular event (adrenal infarction or haemorrhage)

gastric surgery)

Infiltrative disease

Severe illness (septicaemia, liver failure)

Metastatic malignancy

Autoimmune (insulin or insulin receptor antibodies)

Congenital adrenal hyperplasia

• Investigations of hypoglycaemia include:

• Biochemical abnormalities in hypoadrenalism include:

Liver function tests

Hyponatraemia

Ethanol concentration if alcohol abuse is suspected

Hyperkalaemia

Prolonged fasts (up to 72 h) with measurement of

Mild metabolic acidosis

glucose, insulin and C peptide

Anaemia and eosinophilia

Rule out adrenal insufficiency

Mild hypercalcaemia

• Treatment of hypoglycaemia:

• Diagnosis of primary adrenal failure is confirmed by

Acute: conscious, oral glucose; unconscious, intravenous

demonstrating:

glucose and intramuscular glucagon

Subnormal cortisol response to short synacthen test

Chronic: treat the cause

Raised ACTH levels

• Hypoadrenalism should be suspected in individuals with:

Low aldosterone with elevated plasma renin activity

Episodes of hypoglycaemia

Individuals with primary adrenal failure should be

Weight loss

investigated for the cause

Case 21

A 19-year-old man with

sexual dysfunction

Alex consults his GP, at the age of 19, with a history of

His testicles are small measuring 4-5 mL

sexual dysfunction.

He has a small penis measuring 3 cm in length and less than

2 cm in width

What do you want to know at this

He has bilateral gynaecomastia

stage?

Sexual dysfunction is a very common complaint, particu-

What do these findings suggest and

larly in older men. Our patient is a young man and at

what blood tests would you request at

this stage we need to establish:

this stage?

• Is this an intermittent problem? The commonest cause

• The patient is taller than expected (looking at the

of sexual dysfunction is non-organic (psychological) and

height of his parents)

an intermittent nature may be suggestive of this

• He has signs of delayed puberty

diagnosis

Small testicles

• Are there any associated stressful life events?

Underdeveloped penis

• In a young patient, history of pubertal development is

Little facial hair

essential:

• Blood tests to be requested next include

Testicular size

Testosterone

Pubic hair

FSH and LH

Body hair

Voice change

His blood tests show:

Penile development

Testosterone

5 nmol/L (normal range 10-40 nmol/L)

• Previous history

FSH

45 U/L (normal range 0.5-5 U/L)

Systemic illness (mumps can cause primary gonadal

38 U/L (normal range 3-8 U/L)

failure)

Testicular trauma

What do these results suggest?

History of neurological disease: spinal cord disease,

Primary gonadal failure supported by:

multiple sclerosis

• Low testosterone

History of vascular problems

(usually in older

• Raised gonadotrophin

patients)

Chemotherapy

What other questions would you like to

Radiotherapy

ask Alex at this stage?

• History of testicular trauma

On examination:

• History of testicular infection or systemic illness as

Height is 1.95 m (mother 1.67 m, father 1.76 m)

detailed above

He has normal pubic and axillary hair distribution

He has little facial hair (shaves once every 5 days)

There is no significant previous medical history.

What test would you like to request

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

and why?

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

• Chromosomal analysis

146

Case 21

147

Table 37 Differences in testicular failure occurring before and

The patient’s brother, Phil aged 41, with a 3-year history of

after puberty.

T2DM presents with 10 months’ history of erectile

dysfunction. His blood tests show:

Before puberty

After puberty

HbA1c

6.8%

ALT

140 (normal range <40 IU/L)

Testicular volume

<5 mL

<15 mL, soft

630 (normal range 100-300 IU/L)

Penile length

<5 cm

Normal

Bilirubin

14 μmol/L

Sodium

143 mmol/L

Bone age

Delayed

Normal

Potassium

4.3 mmol/L

Body hair

Greatly reduced

Some reduction

Creatinine

78 μmol/L

Voice

High pitched

Normal

Urea

4.3 mmol/L

What would you do now?

A possible diagnosis here is Klinefelter’s syndrome,

• Phil has good diabetes control supported by HbA1c

which is the commonest cause of congenital primary

<7%

hypogonadism, affecting around 1 : 500 men

• He has abnormal liver function manifested as raised

ALT and AP

What are the differences between

• A detailed history is essential, including:

testicular failure occurring before and

Onset and severity: How long has he had the problem

after puberty?

for? Is it intermittent? Can he achieve partial erection?

These are summarized in Table 37. It should be noted that

An abrupt onset of erectile dysfunction, particularly

in some cases the distinction between these two entities

one that is intermittent is often psychogenic in origin

is not that clear.

Presence of night or morning erection: the absence

of morning erection indicates an organic cause rather

Alex’s chromosomal analysis shows that the patient has an

than a psychological problem

extra sex chromosome in XXY pattern.

History of recent stress: which can be associated with

erectile problems and decreased libido

What is the diagnosis?

Associated symptoms of androgen deficiency:

The diagnosis is Kleinfelter’s syndrome. The main clini-

reduced libido, reduced muscle strength, generally

cal features of this syndrome include:

unwell and tired

• Clinical

Sexual dysfunction

Phil tells you that he has had the problem for around a year

Reduced testicular volume

but can still achieve partial erection. Also, he noticed a

Gynaecomastia

decrease in libido in the past few months, which he thought

Female type body composition (eunucoidism)

might be related to his age. His medications include:

Intellectual dysfunction in around half the patients

Metformin 850 mg twice daily

• Biochemical

Simvastatin 40 mg daily

Low testosterone with high gonadotrophins

Aspirin 75 mg daily

XXY karyotype

He undergoes a full examination, which is recorded as

• Treatment

normal.

Androgen replacement: testosterone injections, tes-

tosterone gel, buccal testosterone, testosterone implants

What would you do now?

(rarely used now)

• A history of partial erection is very common in diabe-

tes-related erectile dysfunction

How do you advise this patient

• A decrease in libido may indicate reduced testosterone

regarding fertility?

levels but may also occur during stressful life events

• Most Klinefelter’s patients are infertile

• None of his drugs are associated with erectile dysfunc-

• A minority can produce enough sperm to conceive,

tion. The drugs commonly associated with erectile dys-

but this is rare

function include:

148

Part 2: Cases

Antihypertensives

Table 38 Results of insulin stress test.

Antidepressants

Glucose

Cortisol

Growth hormone

Tranquillizers

(mmol/L)

(nmol/L)

(U/L)

Steroid hormones

Alcohol

0 min

5.1

360

1.2

Heroin and marijuana

Digoxin

30 min

5.3

410

1.5

Anti-androgens

60 min

2.8

530

5.9

• Statin treatment may be responsible for the abnormal

90 min

1.6

740

12.1

liver function and consideration should be given to stop-

ping this treatment or reducing the dose

120 min

1.8

810

25.6

• Metformin treatment can also result in abnormal LFTs

150 min

4.1

820

26.2

but this is less common

180 min

5.2

790

26.3

What tests in relation to erectile

dysfunction would you request?

How do you interpret these results?

The following tests should be requested:

• Insulin stress test shows adequate hypoglycaemia and

• Prolactin

appropriate elevation of cortisol and growth hormone

• Testosterone

(more than 580 nmol/L and 20 U/L respectively) ruling

• FSH and LH

out ACTH and GH deficiency

• TFTs are normal, ruling out TSH deficiency

Blood tests show the following:

• Taken together, Phil has isolated FSH/LH deficiency

Prolactin

211 mU/L (normal <600 mU/L)

as the cause of his hypogonadism

Testosterone

5.6 nmol/L (normal range 10-40 nmol/L)

FSH

2.1 U/L (normal range 0.5-5 U/L)

Would you request any imaging in

0.8 U/L (normal range 3-8 U/L)

this patient?

In view of secondary hypogonadism, pituitary MRI

What do these tests show?

should be requested to rule out a primary pituitary

• Phil has hypogonadotrophic hypogonadism,

sup-

pathology causing hypogonadotrophic hypogonadism.

ported by:

Testosterone levels are very low

MRI of the pituitary is normal. The GP requests one blood

FSH and LH levels are low

test that uncovers the aetiology of Phil’s hypogonadism.

What is the aetiology?

Are these results consistent with

Phil has:

Klinefelter’s syndrome?

• Diabetes

No, in Klinefelter’s gonadotrophins are high.

• Abnormal LFTs

• Hypogonadotrophic hypogonadism

What other tests would you

Therefore, haemochromatosis should be ruled out and

request here?

ferritin levels should be checked.

Full assessment of pituitary function to rule out defi-

ciency of other pituitary hormones (see pp. 3 & 4).

Phil’s ferritin was very high at 1260 ng/mL (normal range

20-200 ng/mL).

Phil undergoes an insulin stress test. The results are shown

in Table 38.

What is the differential diagnosis of

TFTs show:

raised ferritin and what would you do

FT4

16.7 pmol/L

for this patient?

TSH

2.4 mIU/L

The differential diagnosis for raised ferritin includes:

Case 21

149

• Haemochromatosis

Haemochromatosis

• Liver disease (including alcoholism)

Histiocytosis

• Cancers

• Kallman’s syndrome

• Autoimmune conditions

A genetic disorder

The patient should be referred to the haematologist

Associated with anosmia in the majority of patients

for:

• Idiopathic hypogonadotrophic hypogonadism (IHH)

• Full assessment

• Functional

• Treatment

(usually venesection for haemochroma-

Excessive exercise

tosis)

Stress

• Follow-up

Recreational drugs

Systemic illness

The haematologists confirm a diagnosis of

Severe weight changes

haemochromatosis.

How would you treat Phil’s endocrine

problem?

Box 37 Causes of sexual dysfunction

• If fertility is not an issue, simple testosterone replace-

ment should be started

Endocrine causes

• If the patient wants to start a family, the treatment is

• Hypogonadism

more complicated with:

Primary

Human chorionic gonadotrophin (hCG; mimics

Secondary

LH action)

• Thyroid dysfunction

• Diabetes

FSH

• Hyperprolactinaemia

However, this therapy will not be successful if haemo-

chromatosis has also affected the testicles (iron infiltra-

Non-endocrine causes

tion), in which case the patient will have a mixture of

• Drugs

primary and secondary hypogonadism

• Neurological disorders

Spinal cord disease

Multiple sclerosis

What are the causes of secondary

• Vascular disease (generalized atherosclerosis)

hypogonadism (i.e. associated with low

• Penile abnormalities

gonadotrophin levels)?

• Psychogenic

• Infiltrative disease

CASE REVIEW

Alex, aged

19, is complaining of sexual dysfunction.

karyotype. Testosterone replacement should be started in

Although this is a common problem with advancing age,

this patient and issues with fertility discussed as almost all

it is relatively rare in this age group. A careful history and

individuals with Klinefelter’s are infertile.

appropriate physical examination is important to help

The patient’s brother, Phil, a middle-aged gentleman

reach a correct diagnosis. On examination, Alex is found

with T2DM, also presents with a history of erectile

to be tall with little facial hair and small testicles and penis,

dysfunction. This is a common problem in individuals

together with bilateral gynaecomastia. His blood tests are

with diabetes secondary to neuropathic changes and

consistent with primary testicular failure. Taken together,

vascular disease. A detailed history does not give specific

a likely diagnosis is Klinefelter’s syndrome, which is

clues and his medications do not seem to be the cause. His

confirmed on chromosomal analysis showing XXY

blood tests are consistent with secondary gonadal failure

Continued

150

Part 2: Cases

(low testosterone and inappropriately low/low normal

normal pituitary MRI but elevated ferritin levels. This

gonadotrophins). His liver function is abnormal, which

suggests haemochromatosis as a unifying diagnosis for this

may be due to his treatment (statin) but can also be

patient’s hypogonadotrophic hypogonadism

(pituitary

secondary to other pathologies. He undergoes investigations

deposition of iron), abnormal liver function

(liver

of the pituitary axis, and this shows normal cortisol and

deposition) and diabetes

(pancreatic deposition). In

growth hormone response, whereas his prolactin levels and

addition to venesection, Phil will require testosterone or

thyroid functions are normal, indicating isolated

gonadotrophin replacement (the latter is only used when

gonadotrophin deficiency. Further investigations show

fertility is an issue).

KEY POINTS

• Erectile dysfunction is common, particularly in older

Tall stature

individuals, and may be caused by neurological damage,

Intellectual dysfunction in up to half the patients

vascular pathology, androgen deficiency and certain

Reduced testicular volume

medications. It can also be psychological.

Gynaecomastia

• Sexual history is important to establish the correct

• Abnormal blood tests in KS include:

diagnosis, including:

Low testosterone and raised gonadotrophins (primary

Onset and progression (sudden onset erectile

gonadal failure)

dysfunction is usually psychological)

Karyotype: usually XXY

Extent of the problem (partial or complete)

• Other causes of primary hypogonadism include:

Presence of morning erections

Testicular trauma or inflammation (mumps)

Associated medical conditions (vascular disease,

Chemotherapy or radiotherapy

diabetes, spinal cord injuries)

Alcohol excess

Medications

Certain drugs

Social history including recent stress, alcohol,

Cryptorchidism

recreational drugs

Chronic illnesses (renal failure, liver cirrhosis)

• Examination should include:

• Causes of secondary hypogonadism:

Hair distribution

Kallman’s syndrome (frequently associated with

External genitalia

anosmia)

Evidence of associated endocrine or other medical

Idiopathic hypogonadotrophic hypogonadism

conditions

Functional (stress, exercise, weight loss, acute systemic

• Initial investigations for erectile dysfunction should

illness)

include:

Any pituitary pathology

Testosterone, FSH and LH

• Treatment of hypogonadism

Prolactin

Primary: testosterone replacement

Thyroid function tests

Secondary: testosterone replacement (fertility is not a

Fasting glucose

concern); gonadotrophin replacement (to restore

Renal and liver function tests

fertility)

• Klinefelter’s syndrome (KS) is the commonest congenital

cause of primary hypogonadism and is characterized by:

Case 22

A 38-year-old woman with muscular

aches and weakness

Ayesha is a 38-year-old Asian woman who presents with

A detailed history of ‘pins and needles’ to include:

a 2-month history of generalized muscular aches and

• Recent activity (painting and decorating; see above)

weakness, in addition to feelings of pins and needles in her

• Does it follow a particular root or nerve distribution?

hands. Also, she is complaining of difficulties in standing up

For example, in median nerve lesions sensation in

from a squatting position.

the palmar aspect of lateral

3½ fingers are affected,

whereas in ulnar nerve lesions the medial 1½ fingers are

What would you do?

affected

• Generalized aches and pain is a non-specific symptom

and can be due to:

There is no previous history of note and she is not on any

Muscle strain after exertion

medications. She tells you that the feeling of ‘pins and

Myositis

needles’ affects the tips of her fingers and can sometimes

Metabolic abnormalities

be felt around the mouth. Physical examination reveals:

• Pins and needles in the hand may be due to:

No gross neurological abnormality in her upper limbs:

Neurological problem: cervical spondylosis, carpal

normal power, normal sensation to pinprick and touch,

tunnel syndrome

normal reflexes

Metabolic abnormality

Positive Trousseau sign

• Difficulty in standing up from a squatting position

Negative Chvostek’s sign

suggests proximal myopathy, which is found in:

Muscular disorders

What does this suggest?

Neurological disorders

The history and the positive Trousseau sign are sugges-

Endocrine disorders: hyperthyroidism, Cushing’s

tive of hypocalcaemia.

syndrome, hypocalcaemia

• A careful history and examination is important

What test would you request at

A history of exertion (painting and decorating clas-

this stage?

sically causes pain in the shoulder muscles and may

• Calcium profile

cause nerve injury resulting in the sensation of pins

• U&Es

and needles)

Has the patient been started on any drugs? Statins

Her blood test shows:

can cause muscular pains

Sodium

138 mmol/L

• Metabolic abnormalities associated with muscular

Potassium

3.9 mmol/L

pains include:

Creatinine

76 mmol/L

Hyperglycaemia

Urea

3.8 mmol/L

Uraemia

Calcium

1.84 mmol/L (normal range 2.2-2.6 mmol/L)

Hypocalcaemia

640 U/L (normal range 100-300 U/L)

Hypomagnesaemia

What do these results suggest?

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

These results suggest that the cause of Ayesha’s symp-

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

toms is hypocalcaemia.

151

152

Part 2: Cases

What would you do next?

• The cause of her hypocalcaemia should be

established

• Low calcium and raised AP suggests osteomolacia as

the cause

• The following tests should be requested:

PTH

Vitamin D levels

Her blood tests showed:

PTH

15.6 pmol/L (normal range 1-6.1 pmol/L)

Vit D₃

8 ng/L (normal range >60 ng/L)

Figure 63

What is the aetiology of this patient’s

hypocalcaemia?

• This patient’s hypocalcaemia is related to vitamin D

deficiency

What do these results indicate?

• Vitamin D deficiency is common in Asian individuals

• The tests show normalization of her calcium levels and

due to:

PTH, with near normal AP

Diet: low in vitamin D and calcium

• She should continue on her current treatment and

Asian women tend to get less exposure to sunlight

calcium levels should be reassessed in 2-3 months

as the body is covered with clothes

However, we should not automatically assume that

What is the indication for intravenous

hypocalcaemia here is simply due to dietary/cultural

calcium administration?

reasons, particularly in view of the severe disease, and

Intravenous calcium should be avoided if possible as

further investigations may be required

extravasation into the interstitium may cause tissue

necrosis.

Figure 63 is an X-ray of the pelvis/left femur.

• Definite indication for i.v. calcium:

What does the X-ray show?

The X-ray shows Looser zone or pseudofracture (right

femur), which is pathognomic of osteomalacia.

Box 38 Causes of hypocalcaemia

• Primary hypoparathyroidism

What other condition would you like to

Congenital

rule out in this patient?

Autoimmune

Coeliac disease should be ruled out:

Surgical

• Antibodies against transglutaminase (tg) should be

Radiation-related

requested, which are positive in the majority of patients

• Osteomalacia

with coeliac disease

Vitamin D deficiency

Vitamin D resistance

Ayesha’s tg antibodies are positive and coeliac disease is

Malabsorption

further confirmed by endoscopy and duodenal biopsy. She is

• Hypomagnesaemia

started on vitamin D and calcium supplements (Calcichew

• Acute pancreatitis

• Multiple blood transfusion (complexing of calcium with

D3) and a gluten-free diet.

citrate)

She continues on treatment and her calcium profile 8 weeks

• Increased uptake of calcium into the bone

later shows:

Osteoblastic metastasis (such as prostatic metastasis)

Calcium

2.32 mmol/L

Hungry bone syndrome (following parathyroid/thyroid

PTH

4.5 pmol/L

surgery)

320 U/L

Case 22

153

Seizures or tetany in patients with hypocalcaemia

What is a common cause for refractory

Cardiac arrhythmias/arrest with associated

hypocalcaemia failing to respond to

hypocalcaemia

calcium replacement therapy?

• Relative indications

• This may be due to magnesium deficiency

Severely symptomatic patient

• In hypocalcaemic cases, particularly those that are not

Care should be taken to make the infusion into a large

responding to treatment, magnesium levels should be

vein to avoid extravasation.

checked and replacement started as appropriate

CASE REVIEW

Ayesha, a

38-year-old Asian woman, presents with

and raised PTH compatible with a diagnosis of osteomalacia.

months’ history of generalized muscular aches and

An X-ray (pelvis and femur) shows changes compatible

weakness, and pins and needles in her hands, as well as

with Looser zones or pseudofractures, a pathognomic

difficulties in standing up from a squatting position. There

finding in osteomalacia. Although vitamin D-poor diet

is no previous medical history and a detailed history reveals

and lack of sun exposure are common causes of vitamin D

that the sensation of pins and needles can sometimes be

deficiency, all individuals should be investigated for coeliac

felt around the mouth in addition to the finger tips. Her

disease, and it turns out that Ayesha has this condition.

examination shows a positive Trousseau but a negative

Treatment of this patient with a gluten-free diet, together

Chvostek’s sign. The history and examination is suggestive

with vitamin D and calcium supplements, resulted in

of hypocalcaemia, which is confirmed biochemically,

resolution of her symptoms and normalization of her

together with raised alkaline phosphatase, low vitamin D

abnormal biochemistry.

KEY POINTS

• Osteomalacia, a common condition, occurs as a result of

Osteomalacia

inadequate mineralization of mature bone. Rickets is a

Hypomagnesaemia

similar condition but occurs in the growing skeleton

Acute pancreatitis

• Clinical features of osteomalacia include:

Multiple blood transfusions (complexing of calcium with

Bony and muscular aches and pains

citrate)

Fractures

Increased uptake of calcium into the bone: osteoblastic

Proximal myopathy

metastasis (such as prostatic metastasis); hungry bone

Symptoms of hypocalcaemia

syndrome (following parathyroid/thyroid surgery)

• Biochemical findings in osteomalacia include:

• Treatment of osteomalacia includes:

Low vitamin D

Vitamin D and calcium replacement

Low/low-normal calcium

Treat the cause

Raised alkaline phosphatase

• Calcium should be given orally and intravenous calcium is

Raised PTH

only indicated in:

• Causes of low vitamin D levels include:

Seizures or tetany in patients with hypocalcaemia

Poor sunlight exposure

Cardiac arrhythmias/arrest with associated

Poor diet

hypocalcaemia

Malabsorption

Severe symptoms associated with significant

• Causes of hypocalcaemia include:

hypocalcaemia

Primary hypoparathyroidism

Case 23

A wrist fracture in a 56-year-old

woman

Christine, aged 56, suffers a fracture of her wrist after a

Christine had a premature menopause at 39. Her diet is well

minor fall. Her past medical history is unremarkable and she

balanced but she thinks she has hyperthyroidism due to

is not on any regular medication.

episodes of anxiety and palpitations. She is a lifelong

smoker.

What do you need to rule out in this

patient?

How would this help you in

As the fracture happened after a minor fall, the possibility

the diagnosis?

of osteoporosis should be ruled out.

She has a number of risk factors for osteoporosis:

• Early menopause

What questions would you ask this

• Smoking

patient, which may help to diagnose

• Possible hyperthyroidism

osteoporosis?

• History of previous fractures

How can you confirm the presence

• Age at menopause (natural or surgical): earlier age

of osteoporosis?

of menopause is more likely to result in premature

The most widely used technique is dual energy X-ray

osteoporosis

absorptiometry (DEXA)

• Diet: a low calcium/vitamin D diet predisposes an

• Two sites are usually examined:

individual to premature osteoporosis

Femoral neck

• Exercise: minimal activity is associated with premature

Vertebral body

osteoporosis

• Results are expressed as T score

• Smoking: this predisposes to osteoporosis

• Alcohol:

excessive

alcohol

predisposes

Box 39 T score and osteoporosis

osteoporosis

• A history of steroid use (asthma, inflammatory bowel

• T score below −2.5 is indicative of osteoporosis

disease, rheumatoid arthritis): prolonged steroid use

• T score between −1.0 and −2.5 is indicative of

results in osteoporosis

osteopenia (low bone density but not severe enough to

• A history of height loss suggests vertebral crush frac-

be called osteoporosis)

tures, secondary to osteoporosis

• T score higher than −1.0 is regarded as normal

• Previous medical history is important. For example,

the following conditions predispose to osteoporosis:

The DEXA test shows severe osteoporosis in the femoral neck

Hyperthyroidism

(T = −4.4) with normal vertebral bone density (T = +1.2).

Hyperparathyroidism

Cushing’s syndrome

What would you do?

Chronic inflammatory conditions

This discrepancy in bone density may indicate a col-

Gastrointestinal disorders

lapsed fracture of the vertebral body, artificially increas-

ing bone density. Therefore, an X-ray of the back should

be performed.

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

Figure 64 is an X-ray of the back.

154

Case 23

155

Hyperparathyroidism

Growth hormone deficiency

• Gastrointestinal

disorders

associated

with

malabsorption

Coeliac disease

Crohn’s disease

• Neoplastic conditions

Multiple myeloma

• Inflammatory conditions

Rheumatoid arthritis

• Drugs

Steroids

Heparin

Cyclosporine

• Hereditary disorders

Osteogenesis imperfecta

What blood tests would you request

in this patient?

• FBC: anaemia may be a sign of malabsorption

• Plasma viscosity: raised plasma viscosity is found in

multiple myeloma

• U&Es: renal failure may cause osteoporosis

• Calcium profile

• TFTs

Christine’s blood tests showed:

13.2 g/L

WBC

6.7× 10⁹/L

Plat

330× 10⁹/L

1.71

Sodium

137 mmo/L

Potassium

3.8 mmol/L

Figure 64

Urea

4.1 mmol/L

Creatinine

71 μmol/L

What does the X-ray show?

Calcium

2.33 mmol/L

The X-ray shows a fracture of the vertebral body,

107 U/L

explaining the artificially increased bone density in the

FT4

18.4 pmol/L

back.

TSH

1.1 mIU/L

What are the causes of osteoporosis?

• Endocrine disorders

What do these results suggest?

Hypogonadism: in women, early menopause,

All her blood tests are within normal range, suggesting

anorexia nervosa, athletic amenorrhoea, Turner’s syn-

that Christine’s osteoporosis is simply due to:

drome; in men, hypogonadism due to any cause (see

• Premature menopause

Case 9)

• Lifestyle

Cushing’s syndrome

Smoking

Hyperthyroidism

Alcohol

156

Part 2: Cases

Her normal TFTs rule out the possibility of

Calcitonin: can be given as injections or intranasally

hyperthyroidism.

for a short period particularly in the presence of painful

vertebral crush fractures

How would you treat this patient?

Calcitriol

(vitamin 1, 25 dihydroxycholcalciferol):

• In view of her fractures (wrist fracture and vertebral

can be effective but strict monitoring of calcium is

collapse) and the reduced bone density, this patient needs

required as it may induce hypercalcaemia

to start treatment for osteoporosis

PTH analogue: an effective but expensive treatment

• Bisphosphonate with vitamin D₃ and calcium supple-

and can only be given as injections

ments remain the mainstay of treatment. Response to

treatment should be initially monitored by yearly

Box 40 Main side effect of bisphosphonate

densitometry

• Other treatments for osteoporosis include:

• Gastrointestinal disturbances, particularly oesophagitis

Hormone replacement therapy: this is falling out of

• Patients are advised to take the tablet on an empty

favour due to increased risk of breast cancer but is still

stomach with a lot of water and should stay upright for

used in younger patients, with a history of early

at least 2 h after ingestion

• These drugs are usually prescribed once a week

menopause

together with calcium and vitamin D supplements daily

Strontium: is effective in treating osteoporosis but

• Bisphosphonate preparations can be given intravenously,

can make monitoring the response to treatment prob-

with a newer agent given once a year, thereby

lematic (the drug is incorporated into the bone making

simplifying treatment of this condition

DEXA scanning difficult to interpret)

CASE REVIEW

Christine, a woman in her mid-fifties, suffers a wrist

suggests a vertebral collapse, falsely elevating her vertebral

fracture after minor trauma. Due to the circumstances of

density score, a suspicion confirmed on back X-ray which

her fracture (mild trauma), osteoporosis is suspected and

shows collapsed vertebral body, also known as a crush

a careful history is obtained. Christine has a number of risk

fracture. Subsequent investigations show normal blood

factors for osteoporosis including premature menopause,

tests and the possibility of hyperthyroidism is ruled out.

smoking and a history compatible with hyperthyroidism.

Christine is started on bisphosphonate together with

Her dual energy X-ray absorptiometry (DEXA) shows

vitamin D and calcium supplements, which remains the

significant osteoporosis in the femoral neck but an

first-line

treatment for this condition unless

increased bone density in the vertebrae. This discrepancy

contraindicated.

Case 23

157

KEY POINTS

• Osteoporosis, a common condition, is associated with

trauma) or vertebral fractures (sudden onset back pain

both quantitative and qualitative changes in bone

and gradual loss of height)

structure

• Diagnosis

• Causes of osteoporosis include:

Bone densitometry

Endocrine disorders: hypogonadism (in women: early

Routine investigations should be done to rule out

menopause, anorexia nervosa, athletic amenorrhoea,

secondary causes of osteoporosis (particularly in the

Turner’s syndrome; in men: hypogonadism due to any

young)

cause), Cushing’s syndrome, hyperthyroidism,

• Treatment of osteoporosis includes:

hyperparathyroidism, growth hormone deficiency

Bisphosphonate with Vitamin D₃ and calcium

Gastrointestinal disorders associated with

supplements: first choice

malabsorption

Hormone replacement therapy

Multiple myeloma

Strontium

Inflammatory conditions (rheumatoid arthritis)

Calcitonin

Drugs: steroids, heparin, cyclosporine

Calcitriol

Hereditary disorders (osteogenesis imperfecta)

PTH analogue

• Clinical presentation

• Monitoring response to treatment

The disease is usually clinically silent until the occurrence

Regular DEXA scans

of a fracture: peripheral fractures (typically after minor

Occurrence of further fractures

Case 24

A 37-year-old woman with

recurrent flushing

Valerie, aged 37, presents with a 2-month history of

Severity and frequency

recurrent flushing. She has also developed a watery

Predisposing factors

diarrhoea over the past 3-4 weeks, opening her bowels up

Associated symptoms

to six times/day.

• Diarrhoea

What else would you like to know?

Valerie tells you that she can experience flushing up to three

Main causes of flushing include:

times a day and each episode can last from 10-60 min and

• Menopause

is associated with redness in the face. These episodes can

• Pheochromocytoma

occur at any time of the day, but particularly after alcohol

• Carcinoid syndrome

and Indian food.

• Psychological

Causes of diarrhoea include:

What diagnosis would you suspect?

• Infections and infestations

Valerie is describing classical symptoms of carcinoid syn-

Viruses

drome including:

Bacteria

• Flushing and redness in the face, particularly after:

Parasites

Alcohol

Fungi

(particularly in immunocompromised

Spicy food

individuals)

• Diarrhoea

• Malabsorption

Coeliac disease

Pancreatic

disorders

(tumours,

chronic

What is the cause of the carcinoid

pancreatitis)

syndrome?

Gut resection

• Carcinoid syndrome is caused by neuroendocrine

Inflammatory bowel conditions

tumours secreting serotonin and tachykinins leading to

• Overflow diarrhoea (which may occur in the presence

the above symptoms. The presence of symptoms usually

of constipation, particularly in the elderly)

indicates hepatic metastasis

• Endocrine causes:

• Additional symptoms include:

Neuroendocrine tumours

Bronchospasms

Hyperthyroidism

Right ventricular failure (excess serotonin may cause

Diabetes complicated by autonomic neuropathy

right-sided valvular lesions)

• Irritable bowel syndrome

Pellagra-like skin lesions (may develop secondary to

It is important to take a detailed history, concentrating

tryptophan depletion; see below)

on one symptom at a time.

• These tumours can secrete a large number of other

• Flushing

hormones including:

ACTH

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PTH

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

• Tumour location

158

Case 24

159

The vast majority of these tumours are found in the

Radiolabelled meta-iodobenzylguanidine (MIBG)

gastrointestinal tract and they are clinically silent until

they metastasize to the liver

What are the treatment options for

A minority of these tumours originate in the lung

carcinoid tumours?

Other organ involvement is very rare

• In localized disease, surgical treatment may be

curative

What tests would you do to rule out

• Somatostatin analogues (octreotide) can be very effec-

this condition?

tive at controlling the patient’s symptoms

• 24-h urinary 5 hydroxyindole acetic acid (5-HIAA):

• Hepatic embolization: usually palliative

serotonin is synthesized from 5 hydroxytryptophan and

• Interferon therapy

is metabolized to 5-HIAA. Patients should be on a special

Around half the patients respond to this therapy, but

diet to minimize the possibility of false-positive results.

experience with the use of this agent remains limited

For example, banana and chocolate may increase urinary

• Chemotherapy and radiotherapy only have a transient

5-HIAA

effect

• Plasma chromogranin A: a very sensitive marker of the

disease

What is the prognosis of these tumours?

• Carcinoid syndrome is usually ruled out in patients

• Survival of patients with no hepatic metastasis for 5

with normal urinary 5-HIAA and plasma chromogranin

years ranges from 75-90%

• Around a third of patients with hepatic metastasis

survive for 5 years

This patient’s biochemical tests are consistent with a

• Liver transplantation increases 5-year survival to two-

diagnosis of carcinoid syndrome.

thirds in patients with hepatic metastasis

• Patients with hepatic metastasis may survive for as

long as 20, or even 30, years

What would you do next?

The tumour needs to be localized, which can be done

What other types of neuroendocrine

by:

tumours are there?

• Imaging

These are summarized in Table 39.

Ultrasound

What should patients with carcinoid

MRI

syndrome have before surgery?

• Radionucleotide scanning

Octreotide injections are recommended in the periopera-

Radiolabelled octreotide scan as most of these

tive period to reduce the risk of hypotension and

tumours have octreotide receptors

bronchospasm.

Table 39 Neuroendocrine tumour

Tumour

Organs involved Secreted hormone Main symptom(s)

types.

Insulinoma

Pancreas

Insulin

Hypoglycaemia

Gastrinoma

Pancreas

Gastrin

Severe peptic ulcer

disease

Stomach

Intestine

Continued

160

Part 2: Cases

Table 39 Continued

Tumour

Organs involved

Secreted hormone

Main symptom(s)

Glucagonoma

Pancreas

Glucagon

Characteristic skin

rash

Mucous

membrane

involvement

Glucose

intolerance

Diabetes

VIPoma

Pancreas

Vasoactive intestinal

Watery diarrhoea

peptide (VIP)

Somatostatinoma

Pancreas

Somatostatin

Glucose

intolerance

Stomach

Diabetes

Intestine

Diarrhoea

CASE REVIEW

Valerie, who is 37 years old, presents with a short history

This suspicion is confirmed by demonstrating raised 24-h

of flushing and watery diarrhoea. Episodes of flushing can

urinary 5 hydroxyindole acetic acid (5-HIAA) as well as

occur up to three times/day and are associated with redness

plasma chromogranin A. Imaging techniques are necessary

in the face and there seems to be an association with

to localize the tumour and arrange for appropriate

alcohol and spicy food. The history raises the possibility of

treatment.

carcinoid syndrome as a cause for this patient’s symptoms.

KEY POINTS

• Carcinoid is a rare neuroendocrine tumour, which should

Hepatic embolization: usually palliative

be suspected in individuals with a history of:

Immunotherapy: interferon

Flushing: particularly after alcohol or spicy food

Chemotherapy and radiotherapy only have a transient

Diarrhoea

effect

Bronchospasms (can be mistaken for asthma)

• Prognosis is variable with survival up to 90% for 5 years

Right-sided heart lesions

in those with no hepatic metastasis

• Diagnosis is made by demonstrating:

• Other neuroendocrine tumours (all exceedingly rare)

Raised 24-h urinary 5 hydroxyindole acetic acid (5-HIAA)

include:

Raised plasma chromogranin A

Insulinoma: results in hypoglycaemia

• Tumour localization is done by:

Gastrinoma: results in severe peptic ulcer disease

Imaging (ultrasound/CT/MRI)

Glucagonoma

Radionucleotide scanning (octreotide, MIBG)

VIPoma

• Treatment of carcinoid tumours includes:

Somatostatinoma

Surgery may be curative in localized disease

Somatostatin analogues (octreotide) can be effective at

controlling symptoms

Case 25

A 46-year-old man with an abnormal

lipid profile

Oliver, aged 46, is found to have an abnormal lipid profile,

The patient tells you that:

during routine tests prior to employment abroad.

He smokes 10/day

Total cholesterol (TC)

6.5 mmol/L

His father died of myocardial infarction aged 55

Low density lipoprotein cholesterol (LDL)

5.1 mmol/L

He plays football once a week (but not always)

High density lipoprotein cholesterol (HDL)

0.9 mmol/L

He drinks up to 50 units of alcohol a week

Triglycerides

1.4 mmol/L

On examination, his weight is 89 kg (BMI 27) and blood pres-

The patient is asymptomatic.

sure is 169/90 mmHg, and urine dipstick shows protein -,

RBC -, WBC -, Glu -, Nit -.

What would you do?

This patient has high TC, high LDL, high TG and low

What do these results suggest?

HDL.

The patient has multiple risk factors for coronary artery

• High TC and LDL predispose to coronary artery

disease, including:

disease

• Family history

• Low HDL also predisposes to coronary artery disease

• Smoking

• The role of high triglycerides in atherosclerotic disease

• Overweight

is less defined but high triglycerides are probably also a

• Little physical activity

risk factor, particularly as they are associated with low

• Hypertension

HDL

• Excess alcohol

• Very high triglyceride levels can cause pancreatitis

Any associated risk factors should be clarified in this

What tests would you request at

patient, including:

this stage?

• Diabetes mellitus

• Fasting glucose to rule out the possibility of diabetes

• Smoking

• TFTs

(hypothyroidism is associated with raised

• Hypertension

cholesterol)

• Previous history of atherothrombotic disease

• U&Es (renal disease is associated with lipid abnormali-

• Family history of ischaemic heart disease

ties, usually low HDL and raised triglyceride)

• Lifestyle issues:

• LFTs (cholestatic disease is associated with raised

Obesity

cholesterol)

Lack of exercise

• ECG (rule out previous cardiac event or the presence

Alcohol consumption

of left ventricular hypertrophy)

Oliver’s tests show:

Fasting glucose

5.1 mmol/L

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

FT4

16.7 pmol/L

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

TSH

1.9 mU/L

161

162

Part 2: Cases

LFTs

normal

tion,

thereby increasing hepatic cholesterol

U&Es

normal

requirements

ECG

normal

Very rarely used these days

The decision to start medical treatment for hyperlipi-

What would you do now?

daemia can be guided by special tables and computer

This patient has multiple risk factors for coronary artery

programs, that take into account associated risk factors.

disease and the following issues need to be addressed:

• Dietary advice

Give one renal cause for high

Reduce fat in the diet

cholesterol with normal U&Es

Increase fresh fruit and vegetables

• Nephrotic syndrome can result in hyper-

Reduce alcohol

cholesterolaemia

• Weight control through:

• Urine dipstick should be performed in all patients with

Diet

raised cholesterol

Exercise: this can increase HDL levels, thereby offer-

Table 40 summarizes the most widely used antihyper-

ing protection from atherosclerotic disease

lipidaemic agents.

• Modification of other risk factors

Stop smoking: effective at increasing HDL levels

Causes of secondary hyperlipidaemia

Treat high blood pressure (needs more measure-

These are listed in Table 41.

ments to confirm)

• Drug therapy

Duncan is known to suffer from hypertriglyceridaemia and

If the above fails to improve the lipid profile, the fol-

is not compliant with his fibrates treatment. His last check

lowing medications can be used:

of his triglycerides was 6 weeks ago, which showed high

• Statins

levels at 18 mmol/L. He presents with severe epigastric

Inhibit cholesterol synthesis in the liver and are

abdominal pain.

very effective at lowering LDL and proven to reduce

the risk of coronary artery disease. Most commonly

What is the most likely diagnosis?

used are pravastatin, simvastatin, atorvastatin and

The most likely diagnosis is acute pancreatitis secondary

rosuvastatin

to elevated triglyceride levels.

• Ezetimibe

Inhibits cholesterol absorption from the gut, usually

used as an add-on therapy

• Fibrates

Table 40 Antihyperlipidaemic agents.

Effective at reducing triglycerides and to a lesser

extent cholesterol; usually used as second line

Agent

Main use

Side effects

• Nicotinic acid

Effective at increasing HDL and reducing triglycer-

Statins

Raised cholesterol

Myopathy

ide levels

Liver abnormalities

• Bile acid sequestrants

Fibrates

Raised

Myopathy (especially if

Bind to bile acids in the gut inhibiting reabsorp-

triglycerides

used with a statin)

Box 41 Main side effects of statins

Liver abnormalities

Gastrointestinal intolerance

• Muscle related:

Simple aches and pains

Ezetimibe Raised cholesterol

Gastrointestinal intolerance

Myositis: diagnosed by symptoms and a significant

(usually as an

increase in creatine kinase

add-on therapy)

• Rhabdomyolysis: this is very rare

Nicotinic

Low HDL

Flushing

• Liver related

acid

Deranged LFTs (may need to stop statins)

Gastritis

Case 25

163

Table 41 Causes of secondary hyperlipidaemia.

Raised cholesterol

Raised triglycerides

Hypothyroidism

Cushing’s syndrome

Nephrotic syndrome

Chronic renal failure

Drugs (diuretics, steroids)

Drugs (isotretinoin, steroids,

β-blockers)

Poor diet (high in saturated fat) Poor diet and excess alcohol

Pregnancy

Cholestatic liver disease

Diabetes and insulin resistance

CASE REVIEW

Oliver, a middle-aged asymptomatic man, was found to

according to special tables, which offer risk assessment

have elevated cholesterol (high LDL and low HDL) with

taking into account age, cholesterol levels and associated

normal triglyceride levels during routine tests prior to

risk factors.

employment. Both high LDL and low HDL predispose to

Duncan is another middle-aged gentleman with known

cardiovascular disease and associated risk factors should be

hypertriglyceridaemia treated with fibrates. Unfortunately,

clarified. Other risk factors in this patient include smoking,

he is not compliant with his treatment and a recent check

excess alcohol, obesity, family history of ischaemic heart

of his triglycerides showed high levels at 18 mmol/L. He

disease and mild hypertension. Subsequent tests rule out

presents with severe epigastric abdominal pain, and, given

diabetes and secondary causes of hypercholesterolaemia.

the poorly controlled triglycerides, pancreatitis is suspected,

Lifestyle modifications are important to reduce the risk of

which can be confirmed by measuring plasma amylase

cardiovascular disease, which may improve lipid profile and

levels.

blood pressure. Antihyperlipidaemic agents can be started

KEY POINTS

• Hyperlipidaemia is a common condition and can be

Nephrotic syndrome

clinically silent until the development of complications

Drugs

• Individuals with raised cholesterol, particularly in the

Pregnancy

presence of low HDL, are at risk of cardiovascular disease

• Management of hyperlipidaemia

• Individuals with raised triglycerides are at additional risk of

Lifestyle changes are important (stop smoking, reduce

pancreatitis

weight, increase exercise)

• Associated risk factors should be addressed in individuals

• Medical treatment should be started after appropriate risk

with raised cholesterol including:

assessment. Currently used drugs include:

Diabetes mellitus

Statins: effective at lowering cholesterol and proven to

Smoking

reduce the risk of coronary artery disease

Hypertension

Ezetimibe: usually used as an add-on therapy to reduce

Previous history of atherothrombotic disease

cholesterol levels

Family history of cardiovascular disease

Fibrates: effective at reducing triglycerides and to a

Lifestyle issues (obesity, lack of exercise, excess alcohol)

lesser extent cholesterol

• Secondary causes of hyperlipidaemia include:

Nicotinic acid: effective at increasing HDL and reducing

Obstructive liver pathology

triglycerides

MCQs

There are 30 MCQs, each with five answers/statements.

The following statements are true except:

In some cases more than one answer can be correct. You

a. Normal MRI does not rule out the possibility of a

may find some of the questions difficult to answer and

microadenoma

this is deliberate in order to give your brain a chance to

b. Raised prolactin may be due to overtreatment with

do some ‘detective work’, which is an essential compo-

thyroxine

nent of endocrinology.

c. Raised prolactin may be due to treatment with

metoclopramide

d. Raised prolactin may be due to polycystic ovary

1 A 45-year-old woman is referred by her GP with a

syndrome

history of tiredness. Her blood tests show FT4 32.3 pmol/L

e. Pregnancy in this woman should be ruled out as a

(10.0-25.0) and TSH of 9.1 mIU/L (0.2-5.0). She was

cause of her raised prolactin

admitted to hospital 6 weeks earlier with a chest infection,

discharged within 2 days and asked to complete a 5-day

course of antibiotics. She was diagnosed with

3 The following are recognized causes of raised alkaline

hypothyroidism 5 years earlier and has been on treatment

phosphatase of bony origin.

with L-thyroxine 100 mcg/day since. Her TFTs 2 years ago,

whilst on treatment with the same dose of L-thyroxine,

a. Osteoporosis

showed FT4 21.2 pmol/L and TSH 1.8 mIU/L.

b. Coeliac disease

c. Paget’s disease

The most likely cause for the abnormal thyroid result is:

d. Metastatic cancer

a. Poor compliance with thyroxine treatment

e. Renal failure

b. Non-thyroidal illness due to her chest infection

c. Pituitary tumour producing TSH

d. Pituitary thyroid hormone resistance

4 A 37-year-old woman underwent total thyroidectomy

e. Malabsorption due to the development of coeliac

for localized papillary carcinoma measuring 2 cm in

disease

diameter. She presents 1 week later with seizures. Her only

treatment is thyroxine 75 mcg/day and BFZ 2.5 mg as

2 A 35-year-old woman is referred by her GP with 2 years

required for intermittent peripheral oedema.

of amenorrhoea. She has had a long psychiatric history,

Her blood tests show:

but is not currently on any antipsychotics. Her past medical

Hb 13.2, WBC 6.2, Plt 245, Na 136 mmol/L, K 3.7 mmol/L,

history includes autoimmune hypothyroidism and she is

U 5.4 mmol/L, Cr 100 μmol/L, FT4 10.1 pmol/L,

overweight with a BMI of 34. Her prolactin is elevated at

TSH 7.3 mIU/L.

1150 mU/L (normal <600). Her medications include

metoclopramide taken when required and L-thyroxine

The most likely cause for her seizures is:

150 mcg/day. MRI of her pituitary is normal.

a. Hypothyroid encephalopathy due to undertreatment

with thyroxine

b. Cerebral metastasis from her thyroid carcinoma

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

c. Hypocalcaemia due to parathyroid resection during

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

her thyroidectomy

164

MCQs

165

d. Raised intracranial pressure due to a pituitary

c. Treatment with spironolactone

adenoma as part of MEN I

d. Conn’s syndrome

e. Hypomagnesaemia secondary to BFZ treatment

e. Treatment with angiotensin converting enzyme

inhibitors (ACEI)

5 The following are recognized causes of hypercalcaemia

except:

9 In diabetic ketoacidosis, the following statements

are true:

a. Hyperthyroidism

b. Growth hormone deficiency

a. The two main abnormalities are dehydration and

c. Thiazide diuretics

acidosis

d. Vitamin D intoxication

b. Potassium-containing solutions should be

e. Familial hypocalciuric hypercalcaemia (FHH)

withheld until it is certain that the urine flow is

satisfactory

c. Neurological symptoms or signs during

6 The following are recognized causes of hyponatraemia

treatment of DKA may be due to fluid

except:

over-replacement

d. Gastric dilation and gastroparesis are recognized

a. Hypothyroidism

complications

b. Treatment with chlorpropamide

e. All patients with DKA should be covered with

c. Hypoadrenalism

antibiotics as infection is a common precipitating

d. Chest infection

cause

e. Acromegaly

10 In non-ketotic hyperosmolar hyperglycaemia, the

7 A 37-year-old woman presents with a neck mass that

following statements are true:

has been growing slowly over the past 2-3 years and it

now measures around 2 cm in diameter. On examination,

a. Most patients will require antibiotic cover

there is a 2-cm swelling in the left side of the neck,

b. The condition should be aggressively treated

slightly irregular, relatively hard and it moves with

with i.v. fluid and high doses of intravenous

swallowing. She has no palpable cervical lymph nodes. She

insulin

is both clinically and biochemically euthyroid.

c. The prognosis is better than DKA

d. Anticoagulation is contraindicated

The best course of action is:

e. Acidosis is never seen in these patients

a. Reassure that this is probably a thyroid cyst that will

disappear and arrange to see her again in 2-3 months

b. Arrange for urgent thyroid ultrasound to further

11 In Klinefelter’s syndrome, the following statements are

characterize the mass

true except:

c. Perform a fine needle aspiration of the nodule

d. Arrange for an urgent CT scan of the neck and

a. It is the commonest cause of congenital primary

chest

hypogonadism affecting 1 : 500 people

e. Arrange for an urgent thyroid uptake scan

b. It can be associated with anosmia

c. Intellectual dysfunction is common

d. It is associated with an increased risk of breast

8 The following are associated with increased plasma

carcinoma

renin activity (PRA), except:

e. It is associated with increased height

a. Addison’s disease

b. Congestive cardiac failure (CCF)

166

Part 3: Self-assessment

d. An association with hypercalcaemia usually indicates

12 A 40-year-old man presents with a 3-month history of

reduced calcium excretion secondary to high

weight loss, diarrhoea and reduced libido. His past medical

adrenaline levels

history includes gastro-oesophageal reflux disease and he

e. Once the diagnosis is made, patients should be

is currently being treated with omeprazole. His thyroid

started on β-blockers to reduce the risk of a

function shows: FT4 7.2 pmol/L (10-25), TSH 0.82 mU/L

hypertensive crisis

(0.2-6.0).

The next step is:

16 The following statements are correct in relation to

a. Check thyroid peroxidase (TPO) antibodies

Turner’s syndrome:

b. Start on L-thyroxine treatment

c. Urgently investigate pituitary function

a. The karyotype is XXY

d. Arrange for an urgent ultrasound of the thyroid

b. Patients should be screened for cardiac

e. Urgently investigate his gastrointestinal system for

complications

malabsorption

c. Most patients are tall

d. It is characterized by high gonadotrophins

e. Osteoporosis is a common complication

13 A 27-year-old man, previously fit and well, developed

recurrent headaches for 3 months and a few weeks’

history of increased sweating and weight gain. His GP

17 Polycystic ovary syndrome (PCOS) is associated with all

arranged a CT scan of the head, which shows a mass in

the following except:

the pituitary fossa.

a. Increased body weight

Which of the following conditions is he least likely to

b. Impaired glucose tolerance and lipid profile

have?

c. Anovulation

a. Visual field defects

d. Reduced sex hormone binding globulin

b. Hypocalcaemia

e. Raised FSH/LH ratio

c. Hypertension

d. Hyperpigmentation

e. Cranial nerve palsies

18 The following are recognized causes of diabetes except:

a. Haemochromatosis

b. Cystic fibrosis

14 Acromegaly is associated with all the following except:

c. Chronic alcoholism

d. Conn’s syndrome

a. Diabetes or impaired glucose tolerance

e. Cushing’s syndrome

b. Hypokalaemia

c. Increased risk of colonic cancers

d. Sleep apnea

19 A 56-year-old gentleman with type 2 diabetes for 6

e. Carpal tunnel syndrome

years is admitted with severe shortness of breath that

developed over 12-24 h. His medications include

metformin, pioglitazone, simvastatin, ramipril and aspirin,

15 The following statements in relation to

and he has been on this treatment for more than 2 years.

pheochromocytomas are correct:

There is no history of chest pain. His blood tests show a

normal FBC, U&Es and HbA1c of 7.9%.

a. May result in hyperglycaemia

b. A hypertensive crisis can be precipitated by

The most likely cause for this man’s symptoms is:

abdominal examination

a. Silent myocardial infarction resulting in left

c. Can be extra-adrenal in up to 50% of cases

ventricular failure

MCQs

167

b. Treatment with metformin resulting in lactic

c. Addison’s disease

acidosis and compensatory hyperventilation

d. Treatment of cardiac arrhythmias

c. Treatment with pioglitazone resulting in fluid

e. Pituitary adenoma

retention

d. Simvastatin-induced rhabdomyolysis with

consequent renal failure and metabolic acidosis

24 The following abnormality in gonadal function,

e. Ramipril-induced renal dysfunction secondary to

testosterone 3 nmol/L and LH 0.8 U/L, can be caused by

renal artery stenosis

the following conditions:

a. Haemochromatosis

20 In gestational diabetes:

b. Klinefelter’s syndrome

c. Kallman’s syndrome

a. The risk of developing diabetes in later life is around

d. Previous radiotherapy for intracranial tumours

e. Testicular trauma

b. Patients with gestational diabetes who require insulin

treatment will almost always continue to have

diabetes post delivery

25 In diabetes, the following statements are correct:

c. Congenital abnormalities are more prevalent than in

the infants of non-diabetic women

a. Patients with type 2 diabetes never require insulin

d. Gestational diabetes typically improves in the last 6

treatment

weeks of pregnancy

b. Maturity Onset Diabetes of the Young (MODY) is

e. Thiazolidinediones are probably safer to use than

an autosomal recessive condition

insulin as they reduce the risk of hypoglycaemia

c. The majority of type 2 diabetes patients die from

cardiovascular disease

d. Weight loss is a common symptom of type 1

21 Recognized causes of high anion gap metabolic

diabetes

acidosis include:

e. Recognized endocrine causes of diabetes include

acromegaly and Cushing’s syndrome

a. Renal failure

b. Addison’s disease

c. Cushing’s syndrome

26 The following are recognized presentations of

d. Salicylate overdose

autonomic neuropathy in patients with diabetes:

e. Severe diarrhoea

a. Postural hypotension

b. Gustatory sweating (sweating after tasting

22 Recognized causes of metabolic alkalosis include:

food)

c. Vomiting and/or diarrhoea

a. Treatment with diuretics

d. Resting tachycardia

b. Conn’s syndrome

e. Foot ulcers

c. Primary hyperparathyroidism

d. Severe vomiting

e. Medullary thyroid cancer

27 The following statements are correct in relation to

diabetic nephropathy:

23 The following abnormality in thyroid function, FT4

31 pmol/L and TSH <0.05 mU/L, can be caused by any of

a. The presence of microalbuminuria is associated with

these conditions except:

a reduction of cardiovascular risks in patients with

diabetes

a. Thyroid inflammation

b. Microalbuminuria can be reversed by the use of

b. Pregnancy without concomitant thyroid disease

calcium channel-blockers

168

Part 3: Self-assessment

c. The development of diabetic nephropathy protects

c. Orlistat, sibutramine and rimonabant are agents

from diabetic retinopathy

used for treatment of obesity

d. False-positive microalbuminuria may occur in the

d. Obese individuals are at increased risk of both

presence of urinary tract infection (UTI) or after

cardiovascular disease and cancers

exercise

e. Cushing’s syndrome should be excluded in all

e. Blood pressure improves in the majority after the

individuals with a body mass index >30

development of diabetic nephropathy

30 Which of the following statements in relation to

28 A 27-year-old woman has been complaining of

hyperlipidaemia are correct?

episodes of sweating, tremor and nausea for 6 months,

which frequently occur in the morning (before breakfast)

a. Secondary causes of raised cholesterol include

and are relieved by eating. Her father, who is diabetic and

hypothyroidism and obstructive uropathy

on metformin treatment, checked her capillary blood sugar

b. CoA reductase inhibitors (statins) are the best agents

during one of these episodes, which was low at

to lower LDL cholesterol and their use is associated

1.8 mmol/L.

with reduced mortality in high-risk patients,

including subjects with diabetes

Which of the following are recognized causes for this

c. Fibrates are more effective at reducing triglycerides

patient’s symptoms:

than statins

a. Insulinoma

d. Ezetimibe reduces ileal cholesterol absorption but it

b. Ingestion of metformin

is relatively weak when used alone and is best

c. Addison’s disease

combined with a statin

d. Ingestion of sulphonylurea

e. Nicotinic acid is effective at lowering LDL

e. Hyperthyroidism

cholesterol and is frequently used as second line in

cases of intolerance to statins

29 Which of the following statements regarding obesity

are correct?

a. It is commonly due to a single gene mutation

b. Obese individuals are predisposed to type 1 diabetes

EMQs

1 Thyroid

2 Reproductive endocrinology

a. Toxic multinodular goitre or solitary toxic nodule

a. Deep venous thrombosis

b. Graves’ ophthalmopathy

b. Decreased insulin sensitivity (insulin resistance)

c. Thyroiditis

c. Low plasma oestrogen with elevated FSH and LH

d. Small pituitary tumours

d. Amiodarone treatment

e. Polycystic ovary syndrome

e. Low plasma oestrogen and FSH/LH levels

f. Slow relaxing ankle reflexes

f. Spironolactone

g. Intestinal obstruction

g. Osteoporosis

h. High-dose aspirin

h. Klinefelter’s syndrome

i. Hypothyroidism

i. Frusemide

j. Steroids

j. Addison’s disease

k. Lid lag

k. Premature ovarian failure

l. Agranulocytosis

l. Increased insulin sensitivity

m. Radiation therapy for cancers

m. Turner’s syndrome

n. Graves’ disease

n. ↓ TSH and ↑ FT4 levels

o. Osteoporosis

o. Polycystic ovary syndrome

For each of the statements below, choose the most likely

answer from the list above. Each answer may be chosen

once, more than once or not at all.

1. Serious side effects of antithyroid drugs include

1. Polycystic ovary syndrome is commonly asso-

2. Long-term complications of untreated

ciated with

hyperthyroidism include

2. Autoimmunity underpins the aetiology of

3. Hypothermia is a complication of

3. One complication of Turner’s syndrome is

4. Radioactive iodine is the preferred first-line

4. Elevated LH/FSH ratio can be seen in

treatment for

5. Pituitary or hypothalamic causes of amenorrhoea

5. Smoking may cause deterioration in

are characterized by

6. One type of amiodarone-induced thyrotoxicosis

6. Use of oral contraceptive pills increases the

can be treated with

risk of

7. Long-term hypothyroidism can be caused by

7. Menopause is biochemically characterized by

8. The commonest cause of hyperthyroidism is

8. XO karyotype is diagnostic of

9. Thyrotoxicosis with absent uptake of technetium

9. One of the treatment options for polycystic ovary

on thyroid scan is diagnostic of

syndrome is

10. A classical sign of hypothyroidism is

10. In pregnancy, hyperemesis gravidarum can be

associated with

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

169

170

Part 3: Self-assessment

3 Biochemical abnormalities

h. ACTH producing pituitary tumours (Cushing’s disease)

a. Growth hormone producing tumours (acromegaly)

i. Testosterone

b. Primary hypothyroidism

j. Bitemporal hemianopia

c. Hyponatraemia

k. Growth hormone deficiency

d. Primary hypogonadism

l. Dopamine agonists

e. Osteomalacia

m. Radiotherapy

f. Treatment with spironolactone

n. Surgery (usually transphenoidal)

g. Osteoporosis

o. Growth hormone producing pituitary tumours

h. Paget’s disease

(acromegaly)

i. Treatment with acetozolamide

j. Hyperkalaemia

For each of the statements below, choose the most likely

k. Raised bicarbonate (metabolic alkalosis)

answer from the list above. Each answer may be chosen

l. Pituitary tumours producing excess prolactin

once, more than once or not at all.

m. Hypocalcaemia

1. Typical visual field defects with large pituitary

n. Conn’s syndrome

tumours

o. Diabetic ketoacidosis

2. Thin skin is a characteristic feature of

3. An increased risk of colonic malignancy has been

documented with

For each of the statements below, choose the most likely

4. The commonest functioning pituitary tumours are

answer from the list above. Each answer may be chosen

5. Prolactinomas are characterized by good response

once, more than once or not at all.

to medical treatment using

1. Hypercalcaemia with an associated pituitary

6. A known complication of Cushing’s disease is

tumour may be caused by

7. Low blood pressure levels in an individual with a

2. A frequent biochemical abnormality in primary

large pituitary tumour strongly suggests

hypoadrenalism is

8. One hormone that does not require replacement in

3. Hypokalaemia and raised blood pressure are

individuals with complete pituitary failure is

characteristic features of

9. A classical clinical sign in individuals with

4. Very high alkaline phosphatase levels are

Cushing’s syndrome is

characteristics of

10. The best first-line treatment option for non-

5. Secondary causes of raised cholesterol include

functioning pituitary tumours is

6. Cushing’s syndrome can be associated with the

following biochemical abnormality

7. High anion gap metabolic acidosis may be caused by

5 Diabetes mellitus

8. Raised alkaline phosphatase and parathyroid

a. Type 2 diabetes

hormone levels are seen in

b. Cardiovascular disease

9. Syndrome of inappropriate antidiuretic hormone

c. Calcium channel-blockers

secretion is characterized by

d. Hyperosmolar non-ketotic hyperglycaemia

10. Early postoperative complications of thyroid

e. Foot ulcers

surgery include

f. β-blockers

g. Diabetic nephropathy

4 Pituitary

h. Metformin

a. Prolactin producing tumours (prolactinoma)

i. Type 1 diabetes

b. Osteoporosis

j. Heart failure

c. Homonymous hemianopia

k. Pain on walking

d. Metoclopramide

l. Gliclazide

e. Cortisol deficiency

m. Angiotensin converting enzyme inhibitors or

f. Aldosterone

angiotensin receptor blockers

g. Proximal myopathy

n. Maturity onset diabetes of the young (MODY)

EMQs

171

For each of the statements below, choose the most likely

5. In a non-diabetic individual, hypoglycaemia in the

answer from the list above. Each answer may be chosen

presence of high insulin but undetectable C peptide

once, more than once or not at all.

plasma levels is suspicious of

1. A strong family history of diabetes at a young age

6. In a non-diabetic individual, hypoglycaemia in the

is usually found in diabetic individuals with

presence of high insulin and detectable C peptide

2. In addition to osmotic symptoms on presenta-

plasma levels is suspicious of

tion, a short history of weight loss is a recognized

7. Tight glucose control in diabetes is important

feature of

for

3. Obesity is a recognized risk factor for

8. Lactic acidosis is a rare but recognized

4. The first-line medical treatment in overweight type

complication of

2 diabetes patients is

9. A test that helps to distinguish between type 1 and

5. A commonly used medical therapy in diabetes that

type 2 diabetes is

can result in hypoglycaemia is

10. Albumin/creatinine ratio is a useful test for

6. The majority of type 2 diabetes individuals die of

7. The use of thiazolidinedione (glitazone) in diabetes

may result in

7 Endocrine tests

8. The first-line antihypertensive agent to use in

a. Toxic multinodular goitre or solitary toxic nodule

individuals with diabetes is

b. Non-functioning pituitary tumours

9. Peripheral neuropathy increases the risks of

c. High plasma calcium and suppressed PTH levels

10. Angiotensin receptor blockers can be used for the

d. Toxic solitary thyroid adenoma

treatment of

e. Polycystic ovary syndrome

f. Acromegaly

g. High plasma calcium and elevated PTH levels

6 Diabetes mellitus

h. Klinefelter’s syndrome

a. Cushing’s disease

i. Adrenal function

b. Increased endogenous insulin production

j. Thyroiditis

c. Metformin treatment

k. Conn’s syndrome

d. Painful peripheral neuropathy

l. Graves’ ophthalmopathy

e. Prevention from pancreatic cancers

m. Kallman’s syndrome

f. Severe hypoglycaemia in insulin-treated diabetic

n. Cushing’s syndrome

individuals

o. Pituitary function

g. Diagnosis of early diabetic nephropathy

h. Glycosylated haemoglobin levels (HbA1c)

For each of the statements below, choose the most likely

i. Diagnosis of type 1 diabetes

answer from the list above. Each answer may be chosen

j. Exogenous administration of insulin

once, more than once or not at all.

k. Diagnosis of retinopathy

1. Glucagon stimulation and insulin stress test are

l. Prevention from diabetic retinopathy, nephropathy and

used to evaluate

neuropathy

2. Short synacthen test is used to assess

m. Orlistat treatment

3. Raised aldosterone/renin ratio is useful for the diag-

n. Urine dipstick for ketonuria

nosis of

o. Diabetic autonomic neuropathy

4. Glucose tolerance test is used for the diagnosis of

5. Overnight dexamethasone suppression test is used

For each of the statements below, choose the most likely

for the diagnosis of

answer from the list above. Each answer may be chosen

6. Mildly raised prolactin can be found in

once, more than once or not at all.

7. In the presence of normal thyroid function, detection

1. Glucagon injection is an option for

of thyroid stimulating hormone antibodies can be

2. Postural hypotension is a classical finding in

useful for the diagnosis of suspected

3. Testing for GAD antibodies can be used for

8. Hypercalcaemia of malignancy is usually

4. Secondary causes of diabetes include

characterized by

172

Part 3: Self-assessment

9. Low testosterone with low FSH and LH levels and

e. Medullary thyroid cancer

associated anosmia are suggestive of

f. Glucagonoma

10. Low testosterone with elevated FSH and LH levels

g. Von Hippel-Lindau disease

are suggestive of

h. Eating spicy food

i. Ovarian or adrenal virilizing tumours

j. Cushing’s syndrome

8 Medical treatment in diabetes and endocrine

k. Graves’ disease

disease

l. Psychogenic polydipsia

a. Polycystic ovary syndrome

m. Multiple endocrine neoplasia type II (MEN II)

b. Graves’ ophthalmopathy

n. Polycystic ovary disease

c. Painful diabetic peripheral neuropathy

o. Excessive gastrin secretion (gastrinoma)

d. Hypercalcaemia of malignancy

e. Hypercholesterolaemia

f. Conn’s syndrome

For each of the statements below, choose the most likely

g. Growth hormone secreting pituitary tumours

answer from the list above. Each answer may be chosen

h. Renal tubular acidosis

once, more than once or not at all.

i. Hypothyroidism

1. Severe flushing of the face and upper thorax after

j. Excess cortisol production by the adrenal glands

alcohol may be due to

k. Pheochromocytomas

2. The combination of an insulinoma and

l. Gynaecomastia

hyperparathyroidism should raise suspicion of

m. Osteomalacia

3. The combination of pheochromocytoma and

n. Hypertriglyceridaemia

retinal hemangioblastoma suggests a diagnosis of

o. Syndrome of inappropriate antidiuretic hormone

4. Severe peptic ulcer disease that is refractory to

secretion

standard medical treatment should be investigated

for the possibility of

5. The combination of hypercalcaemia and low

For each of the statements below, choose the most likely

urinary calcium excretion is suggestive of

answer from the list above. Each answer may be chosen

6. The combination of rapid weight gain and easy

once, more than once or not at all.

bruising in an individual with newly diagnosed

1. Statins are the best agents to treat

diabetes should raise the suspicion of

2. Fibrates are more effective than statins for the

7. The combination of medullary thyroid cancer and

treatment of

pheochromocytoma suggests a diagnosis of

3. Somatostatin analogues are frequently used for the

8. The combination of a thyroid nodule with raised

treatment of

plasma calcitonin levels suggests a diagnosis of

4. Metyrapone can be used for the treatment of

9. In a euvolemic individual, the combination of

5. Metformin is a treatment option for

hyponatraemia, low plasma osmolarity and high

6. Tricyclic antidepressants are a treatment option for

urine osmolarity suggests a diagnosis of

7. Alpha-blockade is a mandatory treatment for

10. The combination of recent hirsutism, deepning of

8. Fluid restriction is used in the treatment of

voice and clitoromegaly is suggestive of

9. Bisphosphonate is a recognized treatment for

10. Vitamin D is used for the treatment of

9 Combinations

a. Multiple endocrine neoplasia type I (MEN I)

b. Familial hypocalciuric hypercalcaemia

c. Carcinoid syndrome

d. Syndrome of inappropriate antidiuretic hormone

secretion

EMQs

173

2. In a muscular body builder, the finding of low

10 Miscellaneous

testosterone with low normal LH levels is suggestive

a. Primary hypogonadism

b. Spironolactone

3. Severe liver failure may result in acute

c. Anabolic steroid abuse

4. In a pregnant woman with Graves’ disease, the best

d. Vertebral crush fractures

treatment option to control thyroid hormone

e. HMG-CoA reductase inhibitors (statins)

levels is

f. Hirsutism

5. One of the best treatment options for diabetic

g. Low dose radioactive iodine

Charcot’s arthropathy is

h. Increased lean body mass and decreased fat mass

6. Hyperaldosteronism secondary to bilateral adrenal

i. Intra-articular steroid injections of the affected joint

hyperplasia is best treated medically with

j. Propylthiouracil

7. A non-diabetic, normocalcaemic individuals with

k. Renal colic due to calculi

polyuria and polydipsia should be investigated for

l. Hypoglycaemia

the possibility of

m. Diabetes insipidus

8. Sudden onset back pain in an individual with

n. Frusemide

known osteoporosis suggests a diagnosis of

o. Immobilization of the affected joint

9. Growth hormone and testosterone hormone

replacement therapy is associated with

For each of the statements below, choose the most likely

10. Late onset congenital adrenal hyperplasia is a

answer from the list above. Each answer may be chosen

recognized cause of

once, more than once or not at all.

1. Rhabdomyolysis is a rare but recognized

complication of treatment with

SAQs

1 A 28-year old-woman presents with classical symptoms

5 An overweight 23-year-old woman (BMI 29) presents

of hyperthyroidism including tremor, heat intolerance,

with 4 months’ history of secondary amenorrhoea.

palpitations, frequent bowel motions, irritability and

weight loss.

a. What basic tests would help you to reach a

diagnosis?

a. What clues in the history or examination would

b. In the presence of hirsutism, what is the commonest

point towards a diagnosis of Graves’ disease?

diagnosis in this group of patients?

b. What are the indications for a thyroid uptake scan in

such individuals?

6 A 51-year-old woman complains of sudden onset severe

back pain. An X-ray of the spine shows collapse of one of

2 A 41-year-old man has been recently diagnosed with

the lumbar vertebrae and general decrease in bone density

diabetes after a few weeks’ history of osmotic symptoms

is noted, suggesting osteoporosis.

and elevated fasting blood glucose at 15 mmol/L.

What are the common causes of early osteoporosis?

In newly diagnosed diabetes, how can you differentiate

type 1 from type 2 diabetes?

7 A 56-year-old man, who was diagnosed with type 2

diabetes 4 years earlier, is admitted to hospital with

3 A 35-year-old woman presents with visual disturbances.

sudden onset chest pain and shortness of breath. An ECG

A CT scan of the head reveals a large pituitary tumour

shows ST elevation in the anterior leads consistent with a

compressing the optic chiasm.

myocardial infarction.

Describe briefly the clinical assessment of this patient.

What is the best strategy to prevent cardiovascular

disease in individuals with type 2 diabetes?

4 A 25-year-old is found to be hypertensive at

190/105 mmHg during routine clinical examination while

8 A 66-year-old woman is complaining of abdominal pain,

registering with a new doctor. Repeat measurement of

constipation and osmotic symptoms. Her fasting glucose

blood pressure shows a value of 193/104 mmHg.

and kidney function are normal but her calcium is found

to be elevated at 3.05 mmol/L.

a. What are the endocrine causes of secondary

hypertension?

a. What are the causes of hypercalcaemia?

b. When should the diagnosis be suspected?

b. In an individual with severe hypercalcaemia, what is

the best medical treatment?

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

174

MCQs answers

a. This is not an uncommon scenario. Failure to

Total thyroid hormone resistance (both pituitary

comply with thyroxine replacement results in an

and peripheral): again this can produce such a

increase in TSH levels (loss of negative feedback)

biochemical abnormality but the patient is

associated with low FT4. Patients usually

usually clinically hypothyroid (peripheral tissue is

compensate before having their blood test done or

not responding to the effects of thyroxine).

before their review at clinic by taking extra tablets

Normal TFTs 2 years earlier effectively rule out a

of thyroxine, and this results in elevated FT4

diagnosis of thyroid hormone resistance as a

without suppression of TSH as levels of the latter

cause for this patient’s symptoms

require days-weeks to change.

Malabsorption may result in increased thyroxine

Non-thyroidal illness, seen in acutely unwell

requirement in hypothyroid patients, but FT4 is

patients, is characterized by low FT4 with

expected to be low or normal and not elevated. It

inappropriately low/low-normal TSH and can be

should be noted that a large number of

difficult to distinguish from secondary

medications may interfere with thyroxine

hypothyroidism. Therefore, checking TFTs in

absorption including commonly used agents

acutely unwell patients should be avoided unless

such as antacids (Gaviscon) and ferrous

the medical condition is deemed to be

sulphate

thyroid-related.

b. A small pituitary microadenoma producing

A pituitary tumour producing TSH may result in

prolactin without detectable radiological

this biochemical abnormality. However, the patient

abnormalities is always possible (sometimes

is usually hyperthyroid clinically and this picture

the tumour is too small to be visualized by

does not occur in subjects with known

MRI).

hypothyroidism (as the thyroid is unable to

Undertreatment with L-thyroxine may result in

produce thyroid hormones), unless the original

elevated prolactin due to increased secretion of

diagnosis was incorrect.

TRH, which can stimulate prolactin production.

Thyroid hormone resistance is a genetic disease

Therefore, in subjects with raised prolactin, TFTs

due to mutations in the thyroid hormone receptor

should be checked to rule out the possibility of

and can be divided into:

hypothyroidism as a cause for raised prolactin.

Pituitary thyroid hormone resistance: this can

Metoclopramide is a dopamine receptor

produce such a biochemical abnormality due to a

antagonist and can increase prolactin levels. A large

compromised feedback mechanism (thyroid

number of agents can modulate plasma prolactin

hormones are unable to switch off TSH

and these are discussed in the clinical section of

production). The patient is clinically thyrotoxic

this book.

(peripheral tissue responds normally to the

Polycystic ovary disease is a possible diagnosis in

effects of excess thyroid hormones) and there is

this patient, particularly given her weight, which

no history of hypothyroidism

can be associated with mildly raised prolactin

levels. Assessing endometrial thickness helps to

differentiate between microprolactinoma and

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

PCOS, as the endometrium is thin in the former

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

and thick in the latter.

176

MCQs answers

177

Pregnancy should always be excluded as a cause

FHH is associated with raised plasma calcium,

of raised prolactin levels to avoid unnecessary, and

and it is a benign condition that does not require

often embarrassing, investigations.

any treatment.

b, c, d, e. Osteoporosis does not cause elevation of

e. Conditions a, b and d can all cause

alkaline phosphatase (AP) unless it is complicated

hyponatraemia due to inappropriate ADH

by a fracture.

secretion.

Coeliac disease can result in decreased calcium

Hypoadrenalism results in hyponatraemia

and vitamin D absorption and, hence, osteomalacia

through renal salt-wasting (absence of aldosterone).

with elevation of AP.

Acromegaly is not usually associated with

The hallmark of Paget’s disease is elevation of

hyponatraemia.

AP; clinically silent Paget’s disease is often picked

c. This is a young woman with a mass in the neck,

up during routine tests that show elevated AP

which appears to be thyroid-related (moves with

levels.

swallowing). It may be a thyroid cyst but even this

Metastatic cancers can certainly result in elevated

can be malignant, and, therefore, should be

AP through bone destruction.

investigated.

Renal failure is associated with impaired

An urgent ultrasound can be helpful as there are

hydroxylation of vitamin D to its active form,

some ultrasound criteria that make a lesion

resulting in vitamin D deficiency and consequently

suspicious (increased vascularity, hypoechoic

raised AP.

masses and microcalcification are ultrasound

c. Hypothyroidism does not usually cause seizures,

features of malignancy). However, some benign-

particularly in the presence of relatively mild TFT

looking masses on ultrasound may turn out to be

abnormalities as in this patient. Individuals

malignant.

with severe hypothyroidism, resulting in myxo-

CT scan of the neck and chest may be useful in

edema coma, may develop seizures but this is

subjects with thyroid malignancy to establish the

extremely rare.

extent of the disease and it is also helpful in those

Cerebral metastasis is a possibility but the

with suspected retrosternal goitres. However, it is

original tumour is small and it appears to be

unlikely to be that helpful in making the correct

localized, and, therefore, distant metastases are

diagnosis here.

unlikely.

An uptake scan of the thyroid is helpful in cases

Hypocalcaemia post thyroid surgery is a

of thyrotoxicosis and the presence of thyroid

recognized complication and it is the most likely

nodule to determine whether the nodule is hot

diagnosis here.

(increased uptake), in which case malignancy risk

This patient does not have MEN I, which is

is negligible, or cold (decreased uptake) in which

associated with medullary and not papillary thyroid

case the risk of malignancy is significant. An uptake

cancers.

scan is not that helpful in individuals who are

Severe hypomagnesaemia may cause seizures but

euthyroid.

it is unlikely with intermittent bendrofluazide

The best test in this patient is fine needle

therapy. Also, severe hypomagnesaemia is expected

aspiration (FNA) of the thyroid. Those with a

to result in hypokalaemia, which this patient does

benign cytology should have a repeat FNA in 6

not have.

months. Those with undetermined or suspicious

b. Hyperthyroidism may cause mild

cytology should undergo surgery. In patients with

hypercalcaemia by increasing bone resorption.

high clinical suspicion and benign cytology results,

Growth hormone excess and not deficiency is a

it is perhaps safer to ask the surgeon to intervene as

cause of hypercalcaemia.

thyroid FNA can give false-negative results in 5-8%

Thiazide diuretics increase renal calcium

of cases.

reabsorption, thereby resulting in

d. Addison’s disease is associated with raised PRA

hypercalcaemia.

due to low aldosterone production and

Vitamin D increases calcium absorption from

hypotension, which stimulate renal renin

the gut and decreases renal loss.

secretion.

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Part 3: Self-assessment

CCF is associated with decreased renal perfusion,

complications develop in a large number of

and, therefore, increased renin production.

individuals.

c and e are both associated with increased renin

Acidosis is not a feature of this condition but

production.

can be seen secondary to the precipitating

In d, there is independent increased production

condition, such as infection or myocardial

of aldosterone, which switches off renin

infarction.

production.

11.

b. Klinefelter’s syndrome (KS) is the commonest

a, c, d. Patients with DKA are dehydrated due to

congenital hypogonadism and is characterized by

osmotic diuresis and vomiting. They are acidotic

low testosterone and high gonadotrophins

due to an abnormal metabolism of fatty acids

(hypergonadotrophic hypogonadism).

giving rise to ketone bodies.

KS is not associated with anosmia, in contrast to

Potassium-containing solutions should not be

Kallman’s syndrome which is characterized by low

withheld if the patient has low plasma potassium as

testosterone and low gonadotrophins

severe hypokalaemia can result in cardiac

(hypogonadotrophic hypogonadism).

arrhythmias and death. Hypokalaemia complicates

Intellectual dysfunction is seen in around half of

treatment of DKA, as correction of acidosis and

KS patients.

insulin treatment both lower plasma potassium by

The risk of breast carcinoma is increased in these

shifting this electrolyte from the extracellular to the

individuals.

intracellular compartment.

It is associated with increased height due to

The development of neurological symptoms

delayed fusion of bone epiphyses (secondary to low

during treatment of DKA may be due to cerebral

testosterone levels).

oedema that can arise secondary to over-

12.

c. Checking this patient’s TPO antibodies is not

enthusiastic fluid replacement.

helpful as his TFT results are not consistent with

Gastroparesis is a known complication of DKA

primary hypothyroidism.

and should be suspected in individuals who

Starting this patient on L-thyroxine may

continue vomiting, in which case the insertion of a

precipitate an adrenal crisis if his cortisol levels are

nasogastric tube may alleviate symptoms.

low, which may be lethal.

The majority of DKA cases are not precipitated

This patient has low FT4 with inappropriately

by infection, and, therefore, routine cover with

low-normal TSH, suggesting secondary

antibiotics for all patients is not warranted.

hypothyroidism. Furthermore, reduced libido

10.

a. In contrast to DKA, a large proportion of

suggests reduced androgen levels. Weight loss and

patients with non-ketotic hyperosmolar

diarrhoea may be due to cortisol deficiency.

hyperglycaemia have an infection, and, therefore,

Therefore, urgent investigations of his pituitary

cover with antibiotics is advised after appropriate

function are required including static hormonal

septic screening.

tests (prolactin, testosterone, SHBG, FSH and LH)

Most of these patients are elderly and frail, and,

as well as stimulating hormonal tests (glucagon

therefore, aggressive treatment with fluid may push

stimulation test or insulin stress test).

these individuals into heart failure. The safest way

Ultrasound of the thyroid has no role here in the

to manage the fluid status of these individuals is via

management of this patient.

the insertion of a central line with regular

Malabsorption may explain the weight loss and

monitoring of the central venous pressure. Despite

diarrhoea but it offers no explanation for the

very high plasma glucose levels, insulin is required

abnormal thyroid function.

in low concentrations in contrast to DKA

13.

b. Visual field defects, classically bitemporal

patients.

hemianopia, are often associated with large

The prognosis is far worse than DKA as

pituitary tumours causing chiasmatic

mortality can reach 50%, compared to less than 5%

compression.

for DKA patients.

Hypercalcaemia can be seen in acromegaly, but

Anticoagulation is advised for these patients, in

hypocalcaemia is not a complication of pituitary

the absence of contraindications, as thrombotic

tumours.

MCQs answers

179

Hypertension may occur in acromegaly or

Chronic anovulation is a key feature of the

Cushing’s disease.

disease.

Hyperpigmentation can be seen in Cushing’s

Reduced sex hormone binding globulin is related

disease.

to insulin resistance and it is one of the

Cranial nerve palsies may occur with large

mechanisms for hirsutism in these individuals as

pituitary tumours or in those complicated by

low SHGB results in higher levels of free androgens

infarction (pituitary apoplexy).

resulting in hirsutism.

14.

b. Acromegaly can result in impaired glucose

LH/FSH ratio are raised in two-thirds of subjects

tolerance and even frank diabetes.

(not FSH/LH ratio).

Hypokalaemia, which may occur in Cushing’s

18.

d. Haemochromatosis results in pancreatic

disease, is not a recognized complication of

infiltration with iron, consequently leading to

acromegaly.

pancreatic β-cell failure and diabetes.

There is an increased risk of colonic cancers in

Cystic fibrosis also results in pancreatic

these patients, and, therefore, periodical

destruction resulting in the development of

colonoscopy is advised for those above the age of 50.

diabetes.

Sleep apnea is a known complication of this

Chronic alcoholism may cause recurrent

condition due to soft tissue enlargement.

pancreatitis, consequently leading to pancreatic

Carpal tunnel syndrome (CTS) is a known

destruction.

complication of acromegaly. The other endocrine

High aldosterone secondary to Conn’s syndrome

condition that results in CTS is hypothyroidism.

is not a recognized cause for diabetes.

15.

a, b. Pheochromocytoma is a very rare cause of

Cushing’s syndrome may result in diabetes

diabetes.

through the diabetogenic action of high steroid

Abdominal palpation can occasionally precipitate

levels.

a hypertensive crisis due to mechanical pressure on

19.

a. The development of symptoms over a short

the tumour.

period of time suggests an acute or semi-acute

Pheochromocytoma is extra-adrenal in only 10%

event. Individuals with diabetes are at increased

of cases.

risk of myocardial infarction (MI), and silent MI

An association with hypercalcaemia suggests

(no chest pain) is commonly seen in this group

MEN 2, which includes pheochromocytoma,

of patients. Therefore, ‘a’ is the most likely

medullary carcinoma of the thyroid and

answer.

hyperparathyroidism.

Metformin is known to cause lactic acidosis, but

Once the diagnosis is made, patients should be

this is a very rare complication and it only seems to

started on an α-blocker before β-blockers can be

occur in subjects with renal failure, very severe

introduced.

heart failure or those who have an underlying

16.

b, d, e. The karyotype is XO (XXY is Klinefelter’s).

infection. Therefore, metformin is contraindicated

Cardiac complications are not uncommon in

in those with renal disease (usual cut-off is a

Turner’s syndrome, including coarctation of the

creatinine >150 μmol/L). It is also contraindicated

aorta, bicuspid aortic valve, aortic root dilatation

in those with severe heart failure or advanced liver

and hypertension.

disease. Lactic acidosis is a possible diagnosis in

Turner’s patients are typically short.

this patient, particularly if he had an infarct, but it

Turner’s is due to a primary ovarian defect, and,

will not be the main cause of his symptoms

therefore, gonadotrophin levels are elevated (loss of

Thiazolidinedione, including pioglitazone,

negative feedback).

treatment is associated with fluid retention and this

Osteoporosis is a common complication due to

class of agents may, therefore, precipitate heart

the loss of protective effects of oestrogen on bones.

failure. However, the symptoms are usually more

17.

e. Most subjects with PCOS are overweight.

gradual (weeks to months). Also, pioglitazone

Impaired glucose metabolism and abnormal lipid

treatment was initiated more than 2 years ago,

profile, secondary to insulin resistance can be

making this treatment as the primary cause of the

found in these subjects.

patient symptoms unlikely. However, pioglitazone

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Part 3: Self-assessment

treatment may have contributed to the symptoms

Causes of normal anion gap metabolic acidosis

through increased water retention.

include:

Rhabdomyolysis is a very rare complication of

Bicarbonate loss through severe diarrhoea

statin therapy and can indeed result in renal failure.

Renal tubular acidosis

However, there are associated symptoms (severe

Addison’s disease

muscular pain), making this diagnosis unlikely.

Treatment with acetozolamide

Ramipril can indeed result in deterioration in

Therefore, acidosis occurs in b and e but it is of

renal function in those with renal artery stenosis,

normal anion gap.

and this is why U&Es are checked around 1 week

Cushing’s syndrome is characterized by

after starting angiotensin converting enzyme

metabolic alkalosis.

inhibitors to ensure that renal function is stable. In

22.

a, b, d. All diuretics result in metabolic alkalosis

the current case, U&Es were normal, ruling out the

except for acetozolamide (used for the treatment of

possibility of ACEI-induced renal dysfunction as a

glaucoma and high altitude sickness), which results

cause of this patient’s symptoms.

in metabolic acidosis as above.

20.

c. The risk of future diabetes in individuals with

Conn’s syndrome is classically characterized by

a history of gestational diabetes is around

hypokalaemic alkalosis.

30%.

Primary hyperparathyroidism results in

Patients with gestational diabetes frequently

hypercalcaemia without any disturbance in

require treatment with insulin, which is usually

acid-base balance.

stopped after delivery.

Severe vomiting may cause metabolic alkalosis

Congenital abnormalities in children of mothers

through hydrochloric acid loss.

with gestational diabetes are more common than

Medullary thyroid cancers secrete

normoglycaemic mothers and it is one reason why

calcitonin, which has no effect on the acid-base

glycaemic control is kept tight during pregnancy in

balance.

these individuals.

23.

e. Thyroid inflammation (thyroiditis) can be viral

Gestational diabetes does not improve but

or immune (bacterial is very rare), and typically

usually gets worse in the last 6 weeks due to

results in elevated thyroid hormone levels in the

increasing insulin resistance.

blood due to thyroid destruction and release of

Oral hypoglycaemic agents are usually

thyroid hormones into the blood stream (it is not

contraindicated in subjects with gestational

due to excess production). This is usually followed

diabetes due to fears of teratogenicity. Small studies

by a period of hypothyroidism, which may last a

have used metformin and sulphonylureas for the

few weeks to months, after which thyroid function

treatment of these individuals but this is not

recovers. In autoimmune thyroiditis, thyroid

common practice.

function may not recover resulting in permanent

21.

a, d. High anion gap metabolic acidosis essentially

hypothyroidism.

indicates the presence of an extra acid in the blood

In some cases of pregnancy, as well as

that is not normally there. In contrast, normal

trophoblastic tumours, high levels of hCG can

anion gap metabolic acidosis is characterized by a

stimulate the thyroid gland (hCG has similar

disturbance in hydrogen and bicarbonate ion

structure to TSH) causing a thyrotoxic picture

without the presence of ‘an additional’ acid.

usually associated with severe vomiting (known as

Causes of high anion gap metabolic acidosis

hyperemesis gravidarum). Only supportive

include:

treatment is needed and antithyroid drugs are not

Diabetic ketoacidosis

used. This is a self-limiting condition that resolves

Renal failure

spontaneously by week 20 of pregnancy.

Lactic acidosis secondary to: hypoxia, infection,

Addison’s disease can be associated with raised

vascular event (such as myocardial infarction),

TSH levels but not suppressed TSH. The

metformin treatment

mechanism is not entirely clear but is possibly

Poisoning: salicylate, methanol, ethylene

related to deranged thyroid hormone action and

glycol

abnormal feedback on pituitary TSH release.

MCQs answers

181

Cardiac arrhythmias are frequently treated with

Recognized endocrine causes of diabetes include:

amiodarone, an agent that is loved by cardiologists

Acromegaly

and loathed by endocrinologists, and this can cause

Cushing’s syndrome

thyroid dysfunction (hypothyroidism in the

Pheochromocytoma

majority and hyperthyroidism in a minority).

Hyperthyroidism (occurrence of diabetes is rare

Pituitary adenoma is unlikely to cause such an

in this common condition)

abnormality in thyroid function. Pituitary tumours

26.

a, b, c, d. Postural hypotension is a classical

may impair TSH production resulting in low FT4

presentation of autonomic neuropathy, which

with low or inappropriately normal TSH. In TSH

results in dizziness and even syncopy, and this

secreting pituitary tumours, both FT4 and TSH are

typically occurs after standing (patients frequently

elevated.

describe dizzy spells after getting out of bed in the

24.

a, c, d. Low testosterone with low gonadotrophins

morning).

indicate secondary or tertiary hypogonadism

Gustatory sweating is a known complication of

(pituitary or hypothalamic abnormality).

diabetes due to autonomic neuropathy.

Haemochromatosis can result in iron infiltration

Gastrointestinal symptoms due to autonomic

of the pituitary, with subsequent secondary

neuropathy are common and include dysphagia,

hypogonadism. Interestingly, it can also cause

delayed gastric emptying, nausea, vomiting,

primary hypogonadism through testicular iron

diarrhoea and constipation.

infiltration.

Resting tachycardia and fixed heart rate (loss of

Klinefelter’s syndrome is characterized by raised

sinus arrhythmia) can also be related to autonomic

gonadotrophins as the primary defect is in the

neuropathy.

testicles (hypergonadotrophic hypogonadism).

Foot ulcers are usually caused by peripheral

Kallman’s syndrome, a genetic disorder, is

neuropathy and loss of sensation in the feet. It

characterized by failure of gonadotrophin secretion

should be noted that autonomic neuropathy

and is often associated with anosmia.

contributes to foot ulcers through absent

Radiotherapy of the head can cause

sweating, making the feet dry and susceptible to

hypothalamic/pituitary damage resulting in

ulceration.

secondary hypogonadism, commonly associated

Other manifestations of autonomic neuropathy

with impaired production of other pituitary

include:

hormones.

Urinary retention

Testicular trauma may cause primary

Absent sweating

hypogonadism with impaired testosterone

Impotence

production but in this case LH levels are

Defective pupillary reflexes

elevated.

27.

d. The presence of microalbuminuria significantly

25.

c, d, e. Patients with type 2 diabetes are initially

increases the risk of cardiovascular disease.

managed with diet and exercise, with or without

Therefore, these patients should have aggressive

oral hypoglycaemic agents. After varying lengths of

management of their cardiovascular risk factors.

time, the majority of patients end up on insulin

Calcium channel-blockers do not generally affect

treatment secondary to pancreatic β-cell failure.

microalbuminuria, which can be reversed by ACEI

Maturity onset diabetes of the young is a

or ARB, and in some cases a combination of the

monogenic form of diabetes (i.e. caused by a

two agents is used.

mutation in a single gene) and it is an autosomal

Diabetic nephropathy is usually associated with

dominant not recessive condition.

diabetic retinopathy. In fact, microvascular

Cardiovascular disease remains the main cause

complications frequently present together, and,

of mortality in subjects with diabetes, as up to 80%

therefore, any patient with one microvascular

of patients die of this condition.

condition should be carefully examined for other

In addition to osmotic symptoms, type 1

microvascular disease.

diabetes subjects present with a short history of

UTI should be ruled out in any individuals who

weight loss.

have a positive microalbuminuria result. Patients

182

Part 3: Self-assessment

are advised to have the urine collection first thing

Obesity predisposes to type 2 but not type 1

in the morning as exercise can cause

diabetes.

microalbuminuria in the absence of renal disease.

Medical treatment of obesity includes orlistat,

Other causes for false-positive microalbuminuria

which acts locally in the gut by inhibiting lipase

include menstruation, pregnancy, any febrile illness

activity, thereby reducing fat absorption.

and congestive cardiac failure.

Sibutramine is a centrally acting appetite

Blood pressure control tends to worsen after the

suppressant but its use in diabetes is not

development of diabetic nephropathy, and this

widespread as it may result in the development of

further results in worsening in renal function

hypertension. Rimonabant is a cannabinoid

creating a vicious cycle. Therefore, tight blood

receptor-blocker, which results in decreased

pressure control in individuals with diabetic

appetite and a feeling of satiety after a meal. This

nephropathy is of paramount importance to avoid

latter agent is very effective at reducing weight but

further deterioration of renal function.

is associated with the development of depression in

28.

a, c, d. Insulinoma typically presents with episodes

around one in seven patients.

of hypoglycaemia, particularly after prolonged

The risk of cardiovascular disease, cancers and

fasting. Patients usually put on weight as they

respiratory conditions is increased in obese

frequently snack to avoid hypoglycaemic attacks.

individuals.

Mode of action of metformin includes inhibition

Obese patients should only be investigated for

of glucose release from the liver, interference with

Cushing’s syndrome in the presence of strong

gut glucose absorption, in addition to a mild

clinical suspicion of this condition.

insulin sensitizing effect. Therefore, it is not usually

30.

b, c, d. Obstructive uropathy does not cause raised

associated with hypoglycaemia as it does not result

cholesterol. Causes of secondary hyperlipidaemia

in increased insulin production.

include hypothyroidism, obstructive liver disease

Addison’s disease is a recognized cause of

and nephrotic syndrome.

hypoglycaemia due to the absence of

Statins have revolutionized treatment of

corticosteroids.

cardiovascular disease and they are used for both

Agents in the sulphonylurea group increase

primary and secondary prevention.

insulin production by pancreatic β-cells, and,

Fibrates are used first line in individuals with

therefore, can result in hypoglycaemia.

elevated triglycerides and can be combined with a

Hyperthyroidism can result in hyper- not

statin in individuals with combined

hypoglycaemia.

hyperlipidaemia.

29.

c, d. Obesity may be due to single gene mutations

The efficacy of ezetemibe is modest when used

(such as mutation in leptin or its receptor), but

alone and best effects are seen when combined with

these cases are very rare. The main cause of obesity

a statin.

is related to the lifestyle: too little exercise and too

Nicotinic acid is the best agent at raising HDL

much food.

levels, but it is not effective at reducing LDL.

SAQs answers

symptoms of pituitary hormone deficiency, which may

a. Important clues for the diagnosis of Graves’ disease

occur in large functional or non-functional tumours

include: a personal or family history of

(pressure effects on normal pituitary tissue), e.g.

autoimmunity, the presence of a diffuse,

thyroid: tiredness, dry skin, cold intolerance; adrenal:

symmetrical and smooth goitre, and the presence of

tiredness, weight loss, gastrointestinal symptoms, low

extrathyroidal manifestation of the disease including

blood pressure; and sex hormones: reduced libido,

Graves’ ophthalmopathy (GO), pretibial myxoedema

sexual dysfunction in men, menstrual abnormalities in

(usually in combination with GO) or thyroid

women. Fully examine the patient for signs of excess or

acropachy (rare).

reduced hormonal secretion (see section on pituitary

b. Thyroid uptake scan in thyrotoxicosis can be

tumours and pituitary failure).

requested in suspicion of thyroiditis, thyroid

nodule(s) [hot nodule (increased uptake) is very

rarely malignant whereas a cold nodule on a

a. Endocrine causes of hypertension include: Cushing’s

background of Graves’ disease carries a significant

syndrome, acromegaly, Conn’s syndrome,

risk of malignancy], and unclear cases

pheochromocytoma and renal artery stenosis

(thyrotoxicosis in the absence of a goitre).

(consequently resulting in increased renin and

aldosterone production).

b. Diagnosis should be suspected in those with:

Important indicators of type 1 diabetes (T1DM) are:

hypertension at a young age, severe and resistant

young age at diagnosis (but T1DM may occur at any

hypertension and the presence of symptoms and/or

age), absence of obesity (but T1DM may occur in obese

signs suggestive of a secondary pathology.

individuals), personal or family history of

autoimmunity, short history of symptoms (days-few

weeks), history of weight loss, and presence of ketones

a. Pregnancy test, prolactin, sex hormone levels:

on urine dipstick. Autoantibody tests can be useful in

oestradiol, testosterone, SHBG, FSH and LH, and

difficult cases, but can be false-negative in up to 20% of

pelvic ultrasound, which is helpful to establish

T1DM individuals.

ovarian and endometrial pathology and endometrial

thickness.

b. The commonest diagnosis in a non-pregnant young

Examine visual fields for defects and request formal

overweight woman with hirsutism and secondary

visual field testing. Establish in the history any

amenorrhoea is polycystic ovary syndrome. It should

symptoms of hormonal excess in case the tumour is

be stressed that taking a proper history before

functional, e.g. prolactin: galactorrhoea; growth

requesting the blood tests is extremely important to

hormone: changing glove and shoe size, headaches,

establish the correct diagnosis.

increased sweating; and steroids: increase in weight,

easy bruising, proximal myopathy. Establish any

Gonadal abnormalities, premature menopause or

Endocrinology and Diabetes: Clinical Cases Uncovered. By R. Ajjan.

prolonged amenorrhoea or hypogonadism in men.

Published 2009 by Blackwell Publishing, ISBN: 978-1-4051-5726-1

Endocrine disease: Cushing’s syndrome,

185

186

Part 3: Self-assessment

hyperparathyroidism, untreated hyperthyroidism and

growth hormone deficiency. Gastrointestinal

a and b. Pheochromocytoma: 24 urine collection for

conditions: inflammatory bowel disease and

catecholamines (usually 3 collections are required).

malabsorption due to any cause (for example coeliac

Conn’s disease: U&Es (to rule out hypokalaemia),

disease). Neoplastic disease: multiple myeloma. Chronic

aldosterone/renin ratio.

inflammatory conditions: rheumatoid arthritis. Long-

Cushing’s syndrome: one or two of the tests below can

term steroid use.

be requested: overnight or low-dose dexamethasone sup-

pression test, midnight cortisol, 24-h urinary cortisol

measurements.

The risk of myocardial infarction (MI) in a diabetic

individual with no known cardiovascular disease is

similar to that of a non-diabetic with a previous MI.

The aetiology varies according to the clinical status of

It is important to treat a cluster of risk factors in these

the patient.

individuals in order to reduce the risk of future ischemic

Hypovolaemic patient (dehydrated)

events:

• Renal salt loss

• Hyperglycaemia, hypoglycaemic agents

(oral or

• Drugs (diuretics)

insulin) to optimize glycaemic control

• Renal disease (recovery phase of acute renal

• Dyslipidaemia, cholesterol-lowering agents

(usually

failure, relief of bilateral ureteric obstruction, salt

HMG-CoA reductase inhibitors, statins are used)

wasting nephropathy)

• Hypertension, antihypertensive medication

(tight

• Addison’s disease

blood pressure control is important in diabetic individu-

• Gastrointestinal loss

als). First-line agents are angiotensin converting enzyme

• Vomiting

inhibitors

(ACEI) and angiotensin receptor blockers

• Diarrhoea

(ARB)

Hypervolaemic patient (excess water)

• Increased urinary albumin excretion (usually mea-

• Congestive cardiac failure

sured using albumin/creatinine ratio): agents used are

• Liver failure

ACEI and ARB

• Nephrotic syndrome

• Increased coagulation: antiplatelet agents, usually

• Excess water intake: commonly seen in hospitalized

aspirin, are given to high-risk individuals, although

patients, who are given too much intravenous fluid not

recent evidence questions the efficacy of aspirin in dia-

containing salts (such as 5% dextrose)

betes subjects

Euvolaemic patient

• Increased weight: diet and exercise are an important

• Syndrome of inappropriate ADH secretion, character-

part of treatment and in difficult cases weight-reducing

ized by low plasma osmolarity and inappropriately high

agents, and even surgery, can be used

urine osmolarity with increased urinary sodium concen-

trations. Causes include:

• Malignancy

a. Hyperparathyroidism, malignancy, familial

• Respiratory disease (usually chest infections)

hypocalciuric hypercalcaemia, granulomatous

• Central nervous system abnormalities

disease (sarcoidosis), vitamin D intoxication,

(encephalitis, meningitis, vascular event, head

thiazide diuretics, hyperthyroidism, Addison’s

injury)

disease.

• Metabolic: hypothyroidism, acute intermittent

b. Patients with severe hypercalcaemia should be

porphyria

rehydrated first and can then be treated with

• Drugs: a long list including antiepileptic

intravenous bisphosphonates.

treatment, chemotherapy agents, antidiabetic

Other treatment options for resistant hypercalcaemia

medications, psychiatric drugs

include calcitonin and high-dose steroids.

• Idiopathic

Index of cases by diagnosis

Case 1 Diabetic ketoacidosis, 66

Case 14 Amiodarone-induced thyrotoxicosis, 120

Case 2 Thyrotoxicosis, 73

Case 15 Conn’s syndrome, 123

Case 3 Hypercalcaemia of malignancy, 79

Case 16 Type 1 and 2 diabetes mellitus (T1DM and

Case 4 Non-functioning pituitary tumour, 82

T2DM), 126

Case 5 Cushing’s syndrome, 86

Case 17 Paget’s disease, 132

Case 6 Hypothyroidism, 89

Case 18 Thyroid carcinoma, 135

Case 7 Hyperosmolar non-ketotic hyperglycaemia

Case 19 Pheochromocytoma, multiple endocrine

(HONK), 92

neoplasia type II (MEN II), 139

Case 8 Acromegaly, 98

Case 20 Hypoglycaemia, hypoadrenalism, 142

Case 9 Prolactinoma, 102

Case 21 Klinefelter’s syndrome, secondary

Case 10 Pituitary failure, 106

hypogonadism, 146

Case 11 Diabetes insipidus, 109

Case 22 Osteomalacia, 151

Case 12 Syndrome of inappropriate ADH secretion

Case 23 Osteoporosis, 154

(SIADH), 113

Case 24 Carcinoid syndrome, 158

Case 13 Polycystic ovary syndrome (PCOS), 117

Case 25 Hyperlipidaemia, 161

187

Index

Note: page numbers in italics refer to figures

adrenal medulla

in pregnancy

20, 76

and those in bold to tables.

adrenal tumours

6, 30, 35

side effects

16, 74

incidentalomas

35, 175, 186

arginine-vasopressin see antidiuretic hormone

abdominal pain

66-8

pheochromocytoma

139, 140

arterial blood gases (ABG)

abdominal X-ray (AXR)

virilizing

atrial fibrillation, paroxysmal

120

acanthosis nigricans

117

adrenal venous sampling

30, 33

autoimmune disorders

67, 90

acarbose

53, 129

adrenocorticotrophic hormone see ACTH

autonomic neuropathy, diabetic

49, 59, 167,

acetazolamide

180

agranulocytosis

16, 74

181

acromegaly

5-6, 98-101

alcohol intake, excess

6-7, 92, 154, 161,

clinical presentation

5, 82-3, 98-9,

179

β-blockers

75, 139

100

aldosterone

β-cells, pancreatic

complications

100

biosynthesis

destruction

investigations

5, 83, 99

control of secretion

dysfunction

MCQ

166, 179

deficiency

34, 42

bicarbonate

non-pituitary causes

100

excess

32-4

therapy

56, 57, 58, 70, 95

treatment

5-6, 99-100

serum

124

venous/plasma

56, 68

ACTH

1, 2, 30

aldosteronism see hyperaldosteronism

biguanides

abnormalities of secretion

6-8

alkaline phosphatase (AP)

132, 151

bile acid sequestrants

162

congenital adrenal hyperplasia

bony

132, 164, 177

biochemical abnormalities

170

deficiency

8, 10, 82, 106

α-blockers

33, 139

bisphosphonates

ectopic production

4, 6, 7, 31, 86-7

α-cells, pancreatic

hypercalcaemia

26, 80-1

excess

6-8, 82, 86-7

amenorrhoea

102

osteoporosis

28, 156

stimulation test

34, 143-4

causes

102, 103

Paget’s disease

29, 133

Addison’s disease

30, 34, 143-4

hypothalamic

side effects

156

differential diagnosis

142

primary

39, 102

body mass index (BMI)

61, 126

thyroid function tests

180

secondary

39, 102-3, 174, 185

bone isotope scan, Paget’s disease

28, 29, 132,